Literature DB >> 31508418

Proteasome Inhibition Activates Autophagy-Lysosome Pathway Associated With TFEB Dephosphorylation and Nuclear Translocation.

Chunyan Li1,2,3, Xin Wang2,3, Xuezhi Li2,3, Kaixin Qiu1,2,3, Fengjuan Jiao2,3, Yidan Liu1, Qingxia Kong4, Yan Liu2,3, Yili Wu2,3.   

Abstract

Ubiquitin-proteasome pathway (UPS) and autophagy-lysosome pathway (ALP) are the two major protein degradation pathways, which are critical for proteostasis. Growing evidence indicates that proteasome inhibition-induced ALP activation is an adaptive response. Transcription Factor EB (TFEB) is a master regulator of ALP. However, the characteristics of TFEB and its role in proteasome inhibition-induced ALP activation are not fully investigated. Here we reported that the half-life of TFEB is around 13.5 h in neuronal-like cells, and TFEB is degraded through proteasome pathway in both neuronal-like and non-neuronal cells. Moreover, proteasome impairment not only promotes TFEB accumulation but also facilitates its dephosphorylation and nuclear translocation. In addition, proteasome inhibition-induced TFEB accumulation, dephosphorylation and nuclear translocation significantly increases the expression of a number of TFEB downstream genes involved in ALP activation, including microtubule-associated protein 1B light chain-3 (LC3), particularly LC3-II, cathepsin D and lysosomal-associated membrane protein 1 (LAMP1). Furthermore, we demonstrated that proteasome inhibition increases autophagosome biogenesis but not impairs autophagic flux. Our study advances the understanding of features of TFEB and indicates that TFEB might be a key mediator of proteasome impairment-induced ALP activation.

Entities:  

Keywords:  TFEB; TFEB dephosphorylation; TFEB nuclear translocation; autophagy-lysosome pathway; ubiquitin-proteasome pathway

Year:  2019        PMID： 31508418      PMCID： PMC6713995          DOI： 10.3389/fcell.2019.00170

Source DB:  PubMed          Journal:  Front Cell Dev Biol        ISSN： 2296-634X


Introduction

Ubiquitin-proteasome pathway (UPS) and autophagy-lysosome pathway (ALP), the two major pathways for protein degradation, are crucial for proteostasis (Kaganovich et al., 2008). They play a critical role in the maintenance of physiological functions, e.g., cell cycle, apoptosis, stress response, etc. Increasing evidence indicates that there is cross-talk between UPS and ALP. Moreover, the dysregulation of UPS and ALP is observed in a number of diseases, which plays a pivotal role in the pathogenesis of diseases, e.g., Alzheimer’s disease. Growing evidence indicates that proteasome inhibition-induced ALP activation is an adaptive response (Albornoz et al., 2019). However, the mechanism remains elusive. UPS is the principal system for degradation of unneeded or misfolded proteins in mammalian cells (Etlinger and Goldberg, 1977; Ciehanover et al., 1978). The ubiquitination of target proteins is sequentially catalyzed by ATP-dependent ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, and ubiquitin-protein ligase E3, gaining the access to proteasomes (Haas et al., 1982). Proteasome consists of a 20S central catalytic complex and two 19S regulatory complexes (Hough et al., 1987; Arrigo et al., 1988; Dong et al., 2019). The 19S complexes deubiquinate and unfold the target proteins, allowing the proteins entering into the 20S proteasome, where they are rapidly degraded by various proteases (Hough et al., 1987; Arrigo et al., 1988; Dong et al., 2019). Proteasomes exist in both nucleus and cytoplasm, contributing to the degradation of cytosplasmic and nuclear proteins (Peters et al., 1994). UPS impairment is observed in a number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, etc., which promotes the pathogenesis of these diseases. First, UPS impairment leads to the dysregulation of gene expression by reducing the degradation of transcriptional factors, e.g., NF-κB, HIF-1α, NFAT, etc., which contributes to the dysregulation of neurodegenerative disease-associated proteins, e.g., BACE1, RCAN1, TMP21, etc. (Sun et al., 2006; Liu et al., 2011; Ly et al., 2013; Wu and Song, 2013; Wu et al., 2015). In addition, various neurodegenerative disease-associated proteins are degraded via UPS, e.g., BACE1, RCAN1, TMP21, etc. (Qing et al., 2004; Liu et al., 2008; Liu et al., 2009; Wang et al., 2012). Moreover, reduced proteasome activity exacerbates the accumulation of damaged or misfolded proteins, e.g., tau and α-synuclein, which might further contribute to the pathogenesis of neurodegenerative diseases (David et al., 2002; Poppek et al., 2006; Alvarez-Castelao et al., 2014). Autophagy-lysosome pathway is mainly responsible for the degradation of aged or damaged organelles and long-lived proteins, contributing to intracellular quality control. Autophagy is a process delivering intracellular constituents to lysosomes for degradation, which is characterized by the formation of autophagosome (Suzuki and Ohsumi, 2007). Autophagy is categorized into three types, microautophagy, chaperone-mediated autophagy (CMA) and macroautophagy, with distinct mechanistic features. Macroautophagy pathway is the major type of autophagy, which has been greatly characterized compared with the other two types. Macroautophagy (autophagy hereafter) starts with a cup-shaped isolated membrane, which engulfs substrates, protein aggregates or organelles to form a spherical double-membraned structure called autophagosome (Parzych and Klionsky, 2014). A number of autophagy-related proteins are implicated in the formation of autophagosome, e.g., microtubule-associated protein 1B light chain-3 (LC3). Mature LC3 is called as LC3-I, while phosphatidylethanolamine-conjugated LC3-I is called as LC3-II. As LC3-II is persistently associated with autophagosomes, increased LC3-II is commonly used as a marker of autophagy activation (Ohsumi, 2014). Lysosome, formed of a membrane-enclosed vacuole, is an acidic cell apparatus. Lysosomal-associated membrane protein 1 (LAMP1) and lysosomal-associated membrane protein 2 (LAMP2) account for approximately 50% of all lysosome membrane proteins, which act as a marker of the amount and integrity of lysosome. Lysosome mainly contains various acidic proteases, e.g., cathepsin D, which contribute to the degradation of proteins or organelles. Autophagosomes fuse with lysosomes to form autophagolysosomes, in which the cargo substrates, protein aggregates or organelles are degraded by acidic proteases in the lysosome. ALP is constitutively maintained at the basal level. It is regulated by cellular stimuli (e.g., nutrient fluctuation, starvation, and hypoxia), damaged organelles, misfolded protein accumulation-induced unfolded protein response, pathogens, etc. For example, nutrient depletion inactivates mechanistic target of rapamycin (mTOR), contributing to ALP activation (Meley et al., 2006; Wullschleger et al., 2006; Hardie, 2007; Napolitano et al., 2018). Dysregulation of ALP is implicated in the pathogenesis of diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, etc. For example, various Alzheimer’s disease-associated molecules are degraded by ALP, such as APP and BACE2 (Liu et al., 2013; Yang et al., 2013). Autophagy-lysosome pathway is regulated at transcriptional level by a number of transcriptional factors. For example, transcription factor EB (TFEB), transcription factor binding to immunoglobulin heavy constant mu enhancer 3 (TFE3), forkhead box O (FOXO) and E2 transcription factor (E2F) contribute to the regulation of genes implicated in autophagosome induction, formation and maturation, lysosome biogenesis, lysosome function, etc. TFEB, a member of the basic helix-loop-helix leucine-zipper family of transcription factors, is a master regulator of ALP by controlling the expression of genes required for autophagosome formation, lysosome biogenesis and lysosome function (Settembre et al., 2011). The activity of TFEB mainly depends on its phosphorylation status and cytoplasm-nucleus shuttling (Puertollano et al., 2018). The phosphorylated TFEB is mainly located in the cytoplasm under physiological conditions, which is the inactive form of TFEB. Under stress conditions, TFEB is activated by kinase inactivation- and phosphatase activation-mediated dephosphorylation and translocates to the nucleus. For example, upon starvation or lysosomal stress, inactivation of mTOR and concomitant activation of the phosphatase calcineurin promotes TFEB dephosphorylation, resulting in its nuclear translocation (Medina et al., 2015; Napolitano et al., 2018). Subsequently, nuclear TFEB binds to the coordinated lysosomal expression and regulation (CLEAR) element, upregulating the expression of its target genes, e.g., LC3, cathepsin D, and LAMP1, contributing to the increasing activity of ALP (Mizushima, 2007; Zheng et al., 2009; Behrends et al., 2010). A recent study showed that TFEB acetylation also contributes to the activation of lysosome activity (Zhang et al., 2018). In addition, Sha et al. reported that TFEB is degraded by proteasome pathway with a half-life of 4–6 h in Hela cells (Sha et al., 2017). The feature of TFEB in neuronal-like cells has not been characterized although both TFEB and TFEB-mediated ALP play a pivotal role in the maintenance of central nervous system (CNS) functions. Moreover, the dysregulation of TFEB and TFEB-mediated ALP contributes the pathogenesis of various neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease, while increasing TFEB expression or activation attenuates the pathogenesis of neurodegenerative diseases (Martini-Stoica et al., 2016; Cortes and La Spada, 2019). Increasing evidences indicate that there is crosstalk between UPS and ALP (Korolchuk et al., 2009a, b; Nam et al., 2017). Although proteasome inhibition-induced ALP activation is well documented, underlying mechanisms remain elusive. In this study, we reported that the half-life of TFEB is around 13.5 h in neuronal-like cells, and TFEB is degraded through proteasome pathway in both neuronal-like and non-neuronal cells. Moreover, proteasome impairment not only promotes TFEB accumulation but also facilitates its dephosphorylation and nuclear translocation. In addition, proteasome inhibition-induced TFEB accumulation, dephosphorylation and nuclear translocation significantly increases the expression of a number of TFEB downstream genes involved in ALP activation, including LC3, particularly LC3-II, cathepsin D, and LAMP1. Furthermore, we demonstrated that proteasome inhibition increases autophagosome biogenesis but not impairs autophagic flux. Our study advances the understanding of features of TFEB and indicates that TFEB might be a key mediator of proteasome impairment-induced ALP activation.

Materials and Methods

Cell Culture

Human embryonic kidney cells HEK293 and human neuroblastoma cells SH-SY5Y were cultured in high-glucose Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum and 100 U/mL penicillin-streptomycin. All cells were maintained in an incubator at 37°C with 5% CO2.

Pharmacological Treatment

Protein half-life was determined by using a 100 μg/mL cycloheximide (CHX) for 0, 4, 8, 12, 16 or 24 h. Proteasome inhibitor MG-132 was applied for 24 h with the concentration of 0, 10, 15 or 20 μM. In time-course experiments, 15 μM MG-132 was applied for 0, 3, 6, 12 or 24 h. 300 nM Bafilomycin A1 (Baf-A1) was applied for 4 h. Baf-A1 was purchased from Abcam and other drugs were purchased from Sigma-Aldrich. The details were described in previous studies (Settembre et al., 2011; Liu et al., 2013; Wu and Song, 2013; Medina et al., 2015).

Western Blot Analysis

Cells were washed with PBS and lysed in RIPA-Doc buffer (Tris–HCl, 50 mM; NaCl, 150 mM; Triton X-100, 1%; deoxycholate, 1%; and SDS, 0.1%; supplemented with protease inhibitors and phosphatase inhibitors). Cell lysates were centrifuged at 12000 rpm for 30 min to pellet the cellular debris. The cytoplasmic proteins and the nuclear proteins were extracted according to instructions of nuclear and cytoplasmic extraction reagents kit (Beyotime, Beijing, China). The supernatant was diluted in 5x SDS-sample buffer and boiled. After resolved in 10% tris–glycine SDS-PAGE, the proteins were transferred to polyvinylidene fluoride (PVDF-FL) membranes. The membranes were blocked with 5% non-fat milk dissolved in 0.05% Tris–buffered saline with Tween 20 (TBST) for 1 h at room temperature, and incubated with primary antibodies overnight at 4°C. After incubation, the membranes were washed with TBST and incubated with secondary antibodies, anti-rabbit antibody or anti-mouse antibody, for 1 h at room temperature. The quantification was performed by using ImageJ. The following antibodies were used: anti-TFEB (cat. 4240, 1:1000) from Cell Signaling Technologies; anti-β-actin (TA-09, 1:5000) from Zhongshan Golden Bridge Biotechnology; anti-LAMP-1 (H4A3, cat. sc-20011, 1:500) and anti-TMP21 (A-7, cat. sc-137003, 1:500) from Santa Cruz Biotechnology; anti-LC3 (cat. NB100-2220, 1:2000) from Novus Biologicals; anti-β-tubulin (cat. WL01931, 1:500) from Wanleibio; anti-Lamin B (cat. WL01775, 1:500) from Wanleibio; anti-rabbit IgG (2B-2301, 1:5000) or anti-mouse IgG (ZB-2305, 1:5000) from Zhongshan Golden Bridge Biotechnology.

Confocal Microscopy

HEK293 cells transiently transfected with TFEB-GFP were seeded on coverslips. 24 h after transfection, cells were treated with 15 μM MG-132 for 0, 3, 6, and 12 h, respectively. After treatment, cells were fixed in 4% paraformaldehyde (Solarbio; P1110) for 20 min and stained with DAPI (300 nM; Thermo Fisher Scientific) at room temperature for 20 min. Cells were rinsed with PBS and sealed in antifade mounting Medium (Beyotime; P0126). Results were analyzed by using SP8 microscope (Leica Microsystems, Germany).

Quantitative RT-PCR

The RNA was isolated from cells using TRIzol reagent (Invitrogen, United States). First- strand cDNA was synthesized by using FastQuant RT Kit (TIANGEN) according to the manufacturer’s instructions. The newly synthesized cDNA was amplified in a 20 μL reaction by using SYBR green kit (TIANGEN). The reaction was detected by QuantStudio 5 Real-Time PCR System (Thermo Fisher Scientific). The following primers were used to amplify the specific genes: LC3 (Forward: 5′-AGCAGCATCCAACCAAAATC-3′; Reverse: 5′-TGTGTCCG TTCACCAACAG-3′), LAMP-1 (Forward: 5′-CTGCCTTTAAA GCTGCCAAC-3′; Reverse: 5′-TGTTCTCGTCCAGCAGACAC-3′), cathepsin D (Forward: 5′-CTTCGACAACCTGATGCAGC-3′; Reverse: 5′-TACTTGGAGTCTGTGCCACC-3′), β-actin (Forward: 5′-CCTGGCACCCAGCACAAT-3′; Reverse: 5′-GGG CCGGACTCGTCATAC-3′). Amplification conditions were as follows: initial denaturation at 95°C for 15 min, followed by 40 cycles comprising denaturation at 95°C for 10 s, annealing at 60°C for 20 s, and extension at 72°C for 30 s.

Semi-Quantitative RT-PCR

The newly synthesized cDNA was amplified in a 10 μL reaction. The following primers were used to amplify the specific genes: LC3 (Forward: 5′-AGCAGCATCCAACCAAAATC-3′; Reverse: 5′-TGTGTCCGTTCACCAACAG-3′), LAMP-1 (Forward: 5′-CTGCCTTTAAAGCTGCCAAC-3′; Reverse: 5′-TGTTCTCGTCCAGCAGACAC-3′), and β-actin (Forward: 5′-CCTGGCACCCAGCACAAT-3′; Reverse: 5′-GGGCCGG ACTCGTCATAC-3′). Amplification conditions were as follows: initial denaturation at 95°C for 3 min, followed by 25–35 cycles comprising denaturation at 95°C for 30 s, annealing at the optimized temperature for each set of primers for 15 s, and extension at 72°C for 45 s. The final extension was carried out at 72°C for 5 min. The products were analyzed on a 1.0% agarose gel prepared in TAE buffer.

Data Analysis

Quantifications were performed with three or more independent experiments. Values represent mean ± SEM. The data was analyzed by one-way ANOVA followed by Tukey’s test or Student’s t-test. P < 0.05 was considered to be statistically significant.

Results

The Half-Life of TFEB Is Approximately 13.5 h in SH-SY5Y Cells

To determine the turnover rate of TFEB protein in SH-SY5Y cells, 100 μg/mL CHX was applied to halt protein synthesis by blocking the translation of messenger RNA. The cells were harvested at 0 (control), 4, 8, 12, 16, and 24 h after CHX treatment, respectively. Western blot was performed to determine the amount of TFEB in control cells and CHX treated cells (Figure 1A). The relative amount of remaining TFEB in CHX treated cells was calculated according to the amount of TFEB in control cells. The level of TFEB was reduced to 60.36 and 13.54% of the control after CHX treatment for 12 and 24 h, respectively (Figure 1B). Based on the curve, the TFEB reduced to 50% at 13.5 h after CHX treatment. It indicated that the half-life of TFEB is approximately 13.5 h in SH-SY5Y cells.
FIGURE 1

The half-life of Transcription Factor EB is approximately 13.5 h in SH-SY5Y cells. (A) SH-SY5Y cells were treated with 100 μg/mL cycloheximide and were harvested at 0, 4, 8, 12, 16, and 24 h after drug treatment. Cell lysates were separated on 10% SDS-PAGE. TFEB antibody was used to detect TFEB. Actin was detected by its antibody and used as the internal control. (B) TFEB levels were plotted as a percentage of the control (0 h). Values are mean ± SEM; n ≥ 3.

The half-life of Transcription Factor EB is approximately 13.5 h in SH-SY5Y cells. (A) SH-SY5Y cells were treated with 100 μg/mL cycloheximide and were harvested at 0, 4, 8, 12, 16, and 24 h after drug treatment. Cell lysates were separated on 10% SDS-PAGE. TFEB antibody was used to detect TFEB. Actin was detected by its antibody and used as the internal control. (B) TFEB levels were plotted as a percentage of the control (0 h). Values are mean ± SEM; n ≥ 3.

Proteasome Inhibition Promotes TFEB Accumulation and Dephosphorylation

It has been reported that TFEB is degraded by UPS in Hela cells (Sha et al., 2017). To determine whether TFEB is degraded via the UPS in neuronal-like cells, proteasome inhibitor MG-132 was applied to SH-SY5Y cells for 24 h at the doses of 0 (control), 10, 15, and 20 μM, respectively. The efficacy of MG-132 has been validated by its inhibitory effect on TMP21 degradation (Supplementary Figure S1), which has been reported previously (Liu et al., 2008). Compared with that in control cells, total TFEB levels were significantly increased to 1.51 ± 0.08, 1.70 ± 0.13, and 1.75 ± 0.15 fold, respectively (Figures 2A,B). To confirm the effect of MG-132 on TFEB accumulation is not a cell type specific effect, same experiment was performed in HEK293 cells. Consistently, MG-132 significantly increases total TFEB expression to 1.55 ± 0.18, 1.62 ± 0.16, and 1.59 ± 0.12 fold at the doses of 10, 15, and 20 μM, respectively (Figures 2C,D). In time-course experiments, HEK293 cells were treated with 15 μM MG-132 for 0, 3, 6, 12, and 24 h, respectively. The levels of TFEB were increased to 1.56 ± 0.02, 1.58 ± 0.08, 1.87 ± 0.08, and 2.00 ± 0.19 fold, respectively (Figures 2E,F).
FIGURE 2

Proteasome inhibition facilitates TFEB accumulation and dephosphorylation. SH-SY5Y cells (A) or HEK293 cells (C) were treated with MG-132 at indicated dosage. Whole-cell lysates were separated by 10% SDS-PAGE. TFEB was detected by TFEB antibody. Actin served as a loading control. (B,D) Quantification of TFEB shown in (A,C), respectively. (E) HEK293 cells were treated with 15 μM MG-132 for indicated time course. (F) Quantification of TFEB shown in panel (E). Values are mean ± SEM; n ≥ 3, ∗P < 0.05 by one-way ANOVA followed by Tukey’s test.

Proteasome inhibition facilitates TFEB accumulation and dephosphorylation. SH-SY5Y cells (A) or HEK293 cells (C) were treated with MG-132 at indicated dosage. Whole-cell lysates were separated by 10% SDS-PAGE. TFEB was detected by TFEB antibody. Actin served as a loading control. (B,D) Quantification of TFEB shown in (A,C), respectively. (E) HEK293 cells were treated with 15 μM MG-132 for indicated time course. (F) Quantification of TFEB shown in panel (E). Values are mean ± SEM; n ≥ 3, ∗P < 0.05 by one-way ANOVA followed by Tukey’s test. The phosphorylated TFEB (high molecular weight) and dephosphorylated TFEB (low molecular weight) were detected in control cells although dephosphorylated TFEB is much less than phosphorylated TFEB (Figures 2A,C,E). MG-132 treatment significantly shifted TFEB from phosphorylated form to dephosphorylated form (Figures 2A,C,E). In both SH-SY5Y and HEK293 cells, 24-hour MG-132 treatment completely shifts phosphorylated TFEB to dephosphorylated form at the dosage of 10, 15, and 20 μM, respectively (Figures 2A,C). In time-course experiments, phosphorylated TFEB gradually shifts to the dephosphorylated form in a time-dependent manner (Figure 2E). Our data demonstrated that proteasome inhibition not only promotes TFEB accumulation but also shifts TFEB to the dephosphorylated form, indicating that TFEB is degraded by proteasome pathway and proteasome inhibition promotes TFEB dephosphorylation.

Proteasome Inhibition Facilitates TFEB Nuclear Translocation

The subcellular distribution of TFEB mainly depends on its phosphorylation status. Phosphorylated TFEB is mainly located in the cytoplasm, while dephosphorylated TFEB mainly translocates to the nucleus. Our data showed that proteasome inhibition promotes TFEB dephosphorylation, suggesting that proteasome inhibition might promote TFEB nuclear translocation. To confirm this effect, cytoplasmic and nuclear proteins were extracted from control cells and MG-132 treated cells. 24 h after treatment with vehicle or 15 μM MG-132, cytoplasmic and nuclear proteins were extracted and analyzed. No nuclear protein lamin B was detected in the cytoplasmic fraction, while cytoplasmic protein β-tubulin was detected (Figure 3A). As expected, phosphorylated TFEB was detected in the cytoplasmic fraction of control cells, while dephosphorylated TFEB was detected in the MG-132 treated cells although the signal is weak (Figure 3A). In the nuclear fraction, abundant lamin B was detected and extremely weak signal of cytoplasmic protein β-tubulin was detected (Figure 3A). As expected, the large amount of dephosphorylated TFEB was detected in the nuclear fraction of MG-132 treated cells but not in control cells. In MG-132 treated cells, the ratio of nuclear TFEB to cytoplasmic TFEB was significantly increased to 10.03 ± 3.18 fold (Figure 3B). It indicated that proteasome inhibition promotes nuclear translocation of dephosphorylated TFEB.
FIGURE 3

Proteasome inhibition promotes TFEB nuclear translocation. (A) HEK293 cells were treated with 15 μM MG-132 for 24 h. The cell lysates were fractionated into cytoplasmic and nuclear fractions. Both nuclear and cytoplasmic fractions were separated by 10% SDS-PAGE. TFEB was detected by TFEB antibody. β-tubulin was detected by β-tubulin antibody and used as the control of cytoplasmic fraction. Lamin B was detected by lamin B antibody and used as the control of nuclear fraction. (B) Relative ratio of nuclear TFEB to cytoplasmic TFEB. N, nuclear; C, cytoplasmic. Values are mean ± SEM; n ≥ 3, ∗P < 0.05 by Student’s t-test. (C) TFEB-GFP was transfected into HEK293 cells. 24 h after transfection, cells were treated with 15 μM MG-132 for 0, 3, 6, and 12 h, respectively. After fixation, cells were stained with DAPI. Confocal microscope was used to analyze the results. Nuclei were stained with DAPI (blue).

Proteasome inhibition promotes TFEB nuclear translocation. (A) HEK293 cells were treated with 15 μM MG-132 for 24 h. The cell lysates were fractionated into cytoplasmic and nuclear fractions. Both nuclear and cytoplasmic fractions were separated by 10% SDS-PAGE. TFEB was detected by TFEB antibody. β-tubulin was detected by β-tubulin antibody and used as the control of cytoplasmic fraction. Lamin B was detected by lamin B antibody and used as the control of nuclear fraction. (B) Relative ratio of nuclear TFEB to cytoplasmic TFEB. N, nuclear; C, cytoplasmic. Values are mean ± SEM; n ≥ 3, ∗P < 0.05 by Student’s t-test. (C) TFEB-GFP was transfected into HEK293 cells. 24 h after transfection, cells were treated with 15 μM MG-132 for 0, 3, 6, and 12 h, respectively. After fixation, cells were stained with DAPI. Confocal microscope was used to analyze the results. Nuclei were stained with DAPI (blue). To further confirm proteasome inhibition-induced TFEB nuclear translocation, GFP tagged TFEB was transfected into HEK293 cells. 24 h after transfection, 15 μM MG-132 was applied. TFEB was mainly located in the cytoplasm in controls cells (0 h), while MG-132 treatment promoted nuclear translocation of TFEB at 3, 6, and 12 h time points, respectively (Figure 3C). The data indicated that proteasome inhibition promotes nuclear translocation of TFEB.

Proteasome Inhibition Facilitates TFEB-Mediated ALP Activation

Transcription Factor EB is activated by its dephosphorylation and nuclear translocation. To examine whether proteasome inhibition-induced TFEB dephosphorylation and nuclear translocation promotes ALP activation, two downstream targets of TFEB were examined. LC3-II is the marker of autophagosome, while LAMP1 is the marker of lysosome. Total LC3 was significantly increased to 2.76 ± 0.44 fold in MG-132 treated cells compared with that in control cells, while LC3-II was markedly increased to 11.01 ± 0.56 fold (Figures 4A–C). Moreover, LAMP1 was dramatically increased to 1.46 ± 0.08 fold in MG-132 treated cells compared with that in control cells (Figures 4A,D). To explore whether proteasome inhibition-induced TFEB nuclear translocation promotes the transcription of its downstream targets for the biogenesis of autophagosome and lysosome, the mRNA levels of LC3, LAMP1 and cathepsin D were examined by qRT-PCR. The mRNA levels of LC3, LAMP1 and cathepsin D were significantly increased to 5.10 ± 0.42, 2.39 ± 0.05, and 1.55 ± 0.07 fold, respectively (Figures 4E–G). Consistently, semi-quantitative RT-PCR data also showed that the mRNA levels of LC3 and LAMP1 were significantly increased (Supplementary Figure S2).
FIGURE 4

Proteasome inhibition facilitates TFEB-mediated autophagy- lysosome pathway activation. (A) HEK293 cells were treated with 15 μM MG-132 for 24 h. Whole-cell lysates were separated by 12% SDS-PAGE. TFEB was detected by TFEB antibody. LAMP-1 was detected by LAMP-1 antibody. LC3-I and LC3-II were detected by LC3 antibody. Actin served as a loading control. (B–D) Quantification of total LC3, LC3-II and LAMP-1 expression. HEK293 cells were treated with 15 μM MG-132 for 24 h. The mRNA levels of LC3, LAMP1 and cathepsin D (CTSD) were examined by qRT-PCR, shown in (E–G), respectively. (H) HEK293 cells were treated with 15 μM MG-132 for 24 h, and then treated with 300 nM Bafilomycin A1 (Baf-A1) for 4 h. Whole-cell lysates were separated by 12% SDS-PAGE. LC3-I and LC3-II were detected by LC3 antibody. Actin served as a loading control. (I) Quantification of LC3-II. Values are mean ± SEM; n ≥ 3, ∗P < 0.05 by Student’s t-test or by one-way ANOVA followed by Tukey’s test.

Proteasome inhibition facilitates TFEB-mediated autophagy- lysosome pathway activation. (A) HEK293 cells were treated with 15 μM MG-132 for 24 h. Whole-cell lysates were separated by 12% SDS-PAGE. TFEB was detected by TFEB antibody. LAMP-1 was detected by LAMP-1 antibody. LC3-I and LC3-II were detected by LC3 antibody. Actin served as a loading control. (B–D) Quantification of total LC3, LC3-II and LAMP-1 expression. HEK293 cells were treated with 15 μM MG-132 for 24 h. The mRNA levels of LC3, LAMP1 and cathepsin D (CTSD) were examined by qRT-PCR, shown in (E–G), respectively. (H) HEK293 cells were treated with 15 μM MG-132 for 24 h, and then treated with 300 nM Bafilomycin A1 (Baf-A1) for 4 h. Whole-cell lysates were separated by 12% SDS-PAGE. LC3-I and LC3-II were detected by LC3 antibody. Actin served as a loading control. (I) Quantification of LC3-II. Values are mean ± SEM; n ≥ 3, ∗P < 0.05 by Student’s t-test or by one-way ANOVA followed by Tukey’s test. To further investigate that the increase of LC3-II is caused by autophagic flux impairment or increased autophagosome biogenesis, Baf-A1, an inhibitor blocking autophagosome-lysosome fusion, was applied with MG-132. MG-132 significantly increases the level of LC3-II to 12.53 ± 0.78 fold, while Baf-A1 along with MG-132 further increases the level of LC3-II to 24.93 ± 2.47 fold (Figures 4H,I). It demonstrated that proteasome inhibition-induced LC3-II elevation is mediated by increased LC3-II expression but not by the blockade of LC3-II degradation, indicating that proteasome inhibition increases autophagosome biogenesis but not impairs autophagic flux. As short-term (only 3h) MG-132 treatment is enough to initiate irreversible effect on cells, the reversible effect of MG-132 withdrawal on ALP activation has not been examined (Supplementary Figure S3).

Discussion

Sha et al. reported that TFEB is degraded by proteasome pathway with a half-life of 4–6 h in Hela cells (Sha et al., 2017). The turnover rate of TFEB in neuronal-like cells has not been characterized although TFEB is highly expressed in CNS and plays a pivotal role in the maintenance of CNS functions. Here we showed that the half-life of TFEB in SH-SY5Y cells is approximately 13.5 h, suggesting that the degradation rate is lower in SH-SY5Y cells than that in Hela cells. However, it has to be noted that the half-life measurement by S35-labeled pulse-chase strategy has to go through immunoprecipitation, which might contribute to the difference. Consistent with the previous study, we showed that TFEB is degraded by the proteasome pathway in both SH-SY5Y and HEK293. It suggested that the proteasome pathway is a major pathway for TFEB degradation without cell type difference. Although proteasome inhibition-induced ALP activation is well documented, underlying mechanisms remain elusive. Our data showed that proteasome inhibition not only promotes TFEB accumulation but also facilitates TFEB dephosphorylation. It has been reported that proteasome inhibition activates calcineurin which is a major phosphatase contributing to the dephosphorylation of TFEB (Medina et al., 2015). Thus, proteasome inhibition-induced TFEB dephosphorylation might be caused by calcineurin activation. Moreover, phosphorylated TFEB is mainly located in the cytoplasm, while TFEB dephosphorylation facilitates it translocation to the nucleus. Consistently, our data showed that proteasome inhibition-induced TFEB accumulation mainly translocates into the nucleus. Nuclear TFEB binds to the CLEAR element within the promoter region of LC3 and LAMP1 genes contributing to the upregulation of their transcription. As expected, increased levels of LC3, cathepsin D, and LAMP1 mRNA were observed in MG-132 treated cells along with the nuclear translocation of TFEB. It highly indicated that TFEB is key mediator in proteasome inhibition-induced ALP activation. Our data showed that TFEB is a key mediator in proteasome inhibition-induced ALP activation. The impairment of proteasome function is well documented in neurodegenerative diseases, while both the activation of TFEB/ALP and inactivation of TFEB/ALP has been reported in neurodegenerative diseases (Martini-Stoica et al., 2016; Finkbeiner, 2019). Our data indicated that TFEB might play a key role in proteasome impairment-induced ALP activation in neurodegenerative diseases. However, it seems to be in conflict with the fact that proteasome impairment along with the deficiency of TFEB/ALP in neurodegenerative diseases. It has to be noted that the bidirectional alteration of TFEB/ALP might be associated with the stages of diseases, duration of the stress and other regulation pathways. Our data showed that short-term proteasome inhibition significantly activates TFEB-mediated ALP, which might explain the mechanism of TFEB/ALP activation concomitant with proteasome impairment at the early stage of neurodegenerative diseases. However, long-term proteasome impairment might lead to ALP inhibition via various mechanisms. First, compensatory activation of ALP might be exhausted by long-term stress conditions, resulting in ALP impairment. Moreover, other regulation pathways might also contribute to the inhibition of ALP (Cortes and La Spada, 2019). For example, increased activity of GSK3β in AD has been reported in many studies, which might contribute to ALP inhibition by promoting TFEB phosphorylation and subsequent cytoplasmic retention (Ly et al., 2013; Li et al., 2016).

Conclusion

In conclusion, the half-life TFEB is approximately 13.5 h in neuronal-like cells, and TFEB is degraded through proteasome pathway in both neuronal-like and non-neuronal cells. Moreover, proteasome impairment not only promotes TFEB accumulation but also facilitates its dephosphorylation and nuclear translocation. Furthermore, proteasome inhibition-induced TFEB accumulation, dephosphorylation and nuclear translocation significantly increases the expression of a number of TFEB downstream genes involved in ALP activation, including LC3, particularly LC3-II, cathepsin D and LAMP1. Furthermore, we demonstrated that proteasome inhibition increases autophagosome biogenesis but not impairs autophagic flux.

Data Availability

The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher. The uncropped Western blot images can be found in the Supplementary Material.

Author Contributions

YW conceived and designed the study. CL, XW, XL, KQ, and FJ performed the experiments. CL, XW, YiL, QK, and YaL analyzed the data. CL and YW wrote the manuscript. CL, XW, KQ, FJ, YaL, and YW revised the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
  45 in total

1.  Proteasomal degradation of tau protein.

Authors:  Della C David; Robert Layfield; Louise Serpell; Yolanda Narain; Michel Goedert; Maria Grazia Spillantini
Journal:  J Neurochem       Date:  2002-10       Impact factor: 5.372

2.  AMP-activated protein kinase and the regulation of autophagic proteolysis.

Authors:  Daniel Meley; Chantal Bauvy; Judith H P M Houben-Weerts; Peter F Dubbelhuis; Mariette T J Helmond; Patrice Codogno; Alfred J Meijer
Journal:  J Biol Chem       Date:  2006-09-21       Impact factor: 5.157

Review 3.  TOR signaling in growth and metabolism.

Authors:  Stephan Wullschleger; Robbie Loewith; Michael N Hall
Journal:  Cell       Date:  2006-02-10       Impact factor: 41.582

Review 4.  Autophagy: process and function.

Authors:  Noboru Mizushima
Journal:  Genes Dev       Date:  2007-11-15       Impact factor: 11.361

5.  Phosphorylation inhibits turnover of the tau protein by the proteasome: influence of RCAN1 and oxidative stress.

Authors:  Diana Poppek; Susi Keck; Gennady Ermak; Tobias Jung; Alexandra Stolzing; Oliver Ullrich; Kelvin J A Davies; Tilman Grune
Journal:  Biochem J       Date:  2006-12-15       Impact factor: 3.857

6.  Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae.

Authors:  Kuninori Suzuki; Yoshinori Ohsumi
Journal:  FEBS Lett       Date:  2007-03-12       Impact factor: 4.124

7.  Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression.

Authors:  Xiulian Sun; Guiqiong He; Hong Qing; Weihui Zhou; Frederick Dobie; Fang Cai; Matthias Staufenbiel; L Eric Huang; Weihong Song
Journal:  Proc Natl Acad Sci U S A       Date:  2006-11-22       Impact factor: 11.205

Review 8.  AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.

Authors:  D Grahame Hardie
Journal:  Nat Rev Mol Cell Biol       Date:  2007-10       Impact factor: 94.444

9.  Degradation of BACE by the ubiquitin-proteasome pathway.

Authors:  Hong Qing; Weihui Zhou; Michelle A Christensen; Xiulian Sun; Yigang Tong; Weihong Song
Journal:  FASEB J       Date:  2004-08-02       Impact factor: 5.191

10.  Misfolded proteins partition between two distinct quality control compartments.

Authors:  Daniel Kaganovich; Ron Kopito; Judith Frydman
Journal:  Nature       Date:  2008-08-28       Impact factor: 49.962
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  14 in total

Review 1.  The different autophagy degradation pathways and neurodegeneration.

Authors:  Angeleen Fleming; Mathieu Bourdenx; Motoki Fujimaki; Cansu Karabiyik; Gregory J Krause; Ana Lopez; Adrián Martín-Segura; Claudia Puri; Aurora Scrivo; John Skidmore; Sung Min Son; Eleanna Stamatakou; Lidia Wrobel; Ye Zhu; Ana Maria Cuervo; David C Rubinsztein
Journal:  Neuron       Date:  2022-02-07       Impact factor: 17.173

2.  Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

Authors:  Daniel J Klionsky; Amal Kamal Abdel-Aziz; Sara Abdelfatah; Mahmoud Abdellatif; Asghar Abdoli; Steffen Abel; Hagai Abeliovich; Marie H Abildgaard; Yakubu Princely Abudu; Abraham Acevedo-Arozena; Iannis E Adamopoulos; Khosrow Adeli; Timon E Adolph; Annagrazia Adornetto; Elma Aflaki; Galila Agam; Anupam Agarwal; Bharat B Aggarwal; Maria Agnello; Patrizia Agostinis; Javed N Agrewala; Alexander Agrotis; Patricia V Aguilar; S Tariq Ahmad; Zubair M Ahmed; Ulises Ahumada-Castro; Sonja Aits; Shu Aizawa; Yunus Akkoc; Tonia Akoumianaki; Hafize Aysin Akpinar; Ahmed M Al-Abd; Lina Al-Akra; Abeer Al-Gharaibeh; Moulay A Alaoui-Jamali; Simon Alberti; Elísabet Alcocer-Gómez; Cristiano Alessandri; Muhammad Ali; M Abdul Alim Al-Bari; Saeb Aliwaini; Javad Alizadeh; Eugènia Almacellas; Alexandru Almasan; Alicia Alonso; Guillermo D Alonso; Nihal Altan-Bonnet; Dario C Altieri; Élida M C Álvarez; Sara Alves; Cristine Alves da Costa; Mazen M Alzaharna; Marialaura Amadio; Consuelo Amantini; Cristina Amaral; Susanna Ambrosio; Amal O Amer; Veena Ammanathan; Zhenyi An; Stig U Andersen; Shaida A Andrabi; Magaiver Andrade-Silva; Allen M Andres; Sabrina Angelini; David Ann; Uche C Anozie; Mohammad Y Ansari; Pedro Antas; Adam Antebi; Zuriñe Antón; Tahira Anwar; Lionel Apetoh; Nadezda Apostolova; Toshiyuki Araki; Yasuhiro Araki; Kohei Arasaki; Wagner L Araújo; Jun Araya; Catherine Arden; Maria-Angeles Arévalo; Sandro Arguelles; Esperanza Arias; Jyothi Arikkath; Hirokazu Arimoto; Aileen R Ariosa; Darius Armstrong-James; Laetitia Arnauné-Pelloquin; Angeles Aroca; Daniela S Arroyo; Ivica Arsov; Rubén Artero; Dalia Maria Lucia Asaro; Michael Aschner; Milad Ashrafizadeh; Osnat Ashur-Fabian; Atanas G Atanasov; Alicia K Au; Patrick Auberger; Holger W Auner; Laure Aurelian; Riccardo Autelli; Laura Avagliano; Yenniffer Ávalos; Sanja Aveic; Célia Alexandra Aveleira; Tamar Avin-Wittenberg; Yucel Aydin; Scott Ayton; Srinivas Ayyadevara; Maria Azzopardi; Misuzu Baba; Jonathan M Backer; Steven K Backues; Dong-Hun Bae; Ok-Nam Bae; Soo Han Bae; Eric H Baehrecke; Ahruem Baek; Seung-Hoon Baek; Sung Hee Baek; Giacinto Bagetta; Agnieszka Bagniewska-Zadworna; Hua Bai; Jie Bai; Xiyuan Bai; Yidong Bai; Nandadulal Bairagi; Shounak Baksi; Teresa Balbi; Cosima T Baldari; Walter Balduini; Andrea Ballabio; Maria Ballester; Salma Balazadeh; Rena Balzan; Rina Bandopadhyay; Sreeparna Banerjee; Sulagna Banerjee; Ágnes Bánréti; Yan Bao; Mauricio S Baptista; Alessandra Baracca; Cristiana Barbati; Ariadna Bargiela; Daniela Barilà; Peter G Barlow; Sami J Barmada; Esther Barreiro; George E Barreto; Jiri Bartek; Bonnie Bartel; Alberto Bartolome; Gaurav R Barve; Suresh H Basagoudanavar; Diane C Bassham; Robert C Bast; Alakananda Basu; Henri Batoko; Isabella Batten; Etienne E Baulieu; Bradley L Baumgarner; Jagadeesh Bayry; Rupert Beale; Isabelle Beau; Florian Beaumatin; Luiz R G Bechara; George R Beck; Michael F Beers; Jakob Begun; Christian Behrends; Georg M N Behrens; Roberto Bei; Eloy Bejarano; Shai Bel; Christian Behl; Amine Belaid; Naïma Belgareh-Touzé; Cristina Bellarosa; Francesca Belleudi; Melissa Belló Pérez; Raquel Bello-Morales; Jackeline Soares de Oliveira Beltran; Sebastián Beltran; Doris Mangiaracina Benbrook; Mykolas Bendorius; Bruno A Benitez; Irene Benito-Cuesta; Julien Bensalem; Martin W Berchtold; Sabina Berezowska; Daniele Bergamaschi; Matteo Bergami; Andreas Bergmann; Laura Berliocchi; Clarisse Berlioz-Torrent; Amélie Bernard; Lionel Berthoux; Cagri G Besirli; Sebastien Besteiro; Virginie M Betin; Rudi Beyaert; Jelena S Bezbradica; Kiran Bhaskar; Ingrid Bhatia-Kissova; Resham Bhattacharya; Sujoy Bhattacharya; Shalmoli Bhattacharyya; Md Shenuarin Bhuiyan; Sujit Kumar Bhutia; Lanrong Bi; Xiaolin Bi; Trevor J Biden; Krikor Bijian; Viktor A Billes; Nadine Binart; Claudia Bincoletto; Asa B Birgisdottir; Geir Bjorkoy; Gonzalo Blanco; Ana Blas-Garcia; Janusz Blasiak; Robert Blomgran; Klas Blomgren; Janice S Blum; Emilio Boada-Romero; Mirta Boban; Kathleen Boesze-Battaglia; Philippe Boeuf; Barry Boland; Pascale Bomont; Paolo Bonaldo; Srinivasa Reddy Bonam; Laura Bonfili; Juan S Bonifacino; Brian A Boone; Martin D Bootman; Matteo Bordi; Christoph Borner; Beat C Bornhauser; Gautam Borthakur; Jürgen Bosch; Santanu Bose; Luis M Botana; Juan Botas; Chantal M Boulanger; Michael E Boulton; Mathieu Bourdenx; Benjamin Bourgeois; Nollaig M Bourke; Guilhem Bousquet; Patricia Boya; Peter V Bozhkov; Luiz H M Bozi; Tolga O Bozkurt; Doug E Brackney; Christian H Brandts; Ralf J Braun; Gerhard H Braus; Roberto Bravo-Sagua; José M Bravo-San Pedro; Patrick Brest; Marie-Agnès Bringer; Alfredo Briones-Herrera; V Courtney Broaddus; Peter Brodersen; Jeffrey L Brodsky; Steven L Brody; Paola G Bronson; Jeff M Bronstein; Carolyn N Brown; Rhoderick E Brown; Patricia C Brum; John H Brumell; Nicola Brunetti-Pierri; Daniele Bruno; Robert J Bryson-Richardson; Cecilia Bucci; Carmen Buchrieser; Marta Bueno; Laura Elisa Buitrago-Molina; Simone Buraschi; Shilpa Buch; J Ross Buchan; Erin M Buckingham; Hikmet Budak; Mauricio Budini; Geert Bultynck; Florin Burada; Joseph R Burgoyne; M Isabel Burón; Victor Bustos; Sabrina Büttner; Elena Butturini; Aaron Byrd; Isabel Cabas; Sandra Cabrera-Benitez; Ken Cadwell; Jingjing Cai; Lu Cai; Qian Cai; Montserrat Cairó; Jose A Calbet; Guy A Caldwell; Kim A Caldwell; Jarrod A Call; Riccardo Calvani; Ana C Calvo; Miguel Calvo-Rubio Barrera; Niels Os Camara; Jacques H Camonis; Nadine Camougrand; Michelangelo Campanella; Edward M Campbell; François-Xavier Campbell-Valois; Silvia Campello; Ilaria Campesi; Juliane C Campos; Olivier Camuzard; Jorge Cancino; Danilo Candido de Almeida; Laura Canesi; Isabella Caniggia; Barbara Canonico; Carles Cantí; Bin Cao; Michele Caraglia; Beatriz Caramés; Evie H Carchman; Elena Cardenal-Muñoz; Cesar Cardenas; Luis Cardenas; Sandra M Cardoso; Jennifer S Carew; Georges F Carle; Gillian Carleton; Silvia Carloni; Didac Carmona-Gutierrez; Leticia A Carneiro; Oliana Carnevali; Julian M Carosi; Serena Carra; Alice Carrier; Lucie Carrier; Bernadette Carroll; A Brent Carter; Andreia Neves Carvalho; Magali Casanova; Caty Casas; Josefina Casas; Chiara Cassioli; Eliseo F Castillo; Karen Castillo; Sonia Castillo-Lluva; Francesca Castoldi; Marco Castori; Ariel F Castro; Margarida Castro-Caldas; Javier Castro-Hernandez; Susana Castro-Obregon; Sergio D Catz; Claudia Cavadas; Federica Cavaliere; Gabriella Cavallini; Maria Cavinato; Maria L Cayuela; Paula Cebollada Rica; Valentina Cecarini; Francesco Cecconi; Marzanna Cechowska-Pasko; Simone Cenci; Victòria Ceperuelo-Mallafré; João J Cerqueira; Janete M Cerutti; Davide Cervia; Vildan Bozok Cetintas; Silvia Cetrullo; Han-Jung Chae; Andrei S Chagin; Chee-Yin Chai; Gopal Chakrabarti; Oishee Chakrabarti; Tapas Chakraborty; Trinad Chakraborty; Mounia Chami; Georgios Chamilos; David W Chan; Edmond Y W Chan; Edward D Chan; H Y Edwin Chan; Helen H Chan; Hung Chan; Matthew T V Chan; Yau Sang Chan; Partha K Chandra; Chih-Peng Chang; Chunmei Chang; Hao-Chun Chang; Kai Chang; Jie Chao; Tracey Chapman; Nicolas Charlet-Berguerand; Samrat Chatterjee; Shail K Chaube; Anu Chaudhary; Santosh Chauhan; Edward Chaum; Frédéric Checler; Michael E Cheetham; Chang-Shi Chen; Guang-Chao Chen; Jian-Fu Chen; Liam L Chen; Leilei Chen; Lin Chen; Mingliang Chen; Mu-Kuan Chen; Ning Chen; Quan Chen; Ruey-Hwa Chen; Shi Chen; Wei Chen; Weiqiang Chen; Xin-Ming Chen; Xiong-Wen Chen; Xu Chen; Yan Chen; Ye-Guang Chen; Yingyu Chen; Yongqiang Chen; Yu-Jen Chen; Yue-Qin Chen; Zhefan Stephen Chen; Zhi Chen; Zhi-Hua Chen; Zhijian J Chen; Zhixiang Chen; Hanhua Cheng; Jun Cheng; Shi-Yuan Cheng; Wei Cheng; Xiaodong Cheng; Xiu-Tang Cheng; Yiyun Cheng; Zhiyong Cheng; Zhong Chen; Heesun Cheong; Jit Kong Cheong; Boris V Chernyak; Sara Cherry; Chi Fai Randy Cheung; Chun Hei Antonio Cheung; King-Ho Cheung; Eric Chevet; Richard J Chi; Alan Kwok Shing Chiang; Ferdinando Chiaradonna; Roberto Chiarelli; Mario Chiariello; Nathalia Chica; Susanna Chiocca; Mario Chiong; Shih-Hwa Chiou; Abhilash I Chiramel; Valerio Chiurchiù; Dong-Hyung Cho; Seong-Kyu Choe; Augustine M K Choi; Mary E Choi; Kamalika Roy Choudhury; Norman S Chow; Charleen T Chu; Jason P Chua; John Jia En Chua; Hyewon Chung; Kin Pan Chung; Seockhoon Chung; So-Hyang Chung; Yuen-Li Chung; Valentina Cianfanelli; Iwona A Ciechomska; Mariana Cifuentes; Laura Cinque; Sebahattin Cirak; Mara Cirone; Michael J Clague; Robert Clarke; Emilio Clementi; Eliana M Coccia; Patrice Codogno; Ehud Cohen; Mickael M Cohen; Tania Colasanti; Fiorella Colasuonno; Robert A Colbert; Anna Colell; Miodrag Čolić; Nuria S Coll; Mark O Collins; María I Colombo; Daniel A Colón-Ramos; Lydie Combaret; Sergio Comincini; Márcia R Cominetti; Antonella Consiglio; Andrea Conte; Fabrizio Conti; Viorica Raluca Contu; Mark R Cookson; Kevin M Coombs; Isabelle Coppens; Maria Tiziana Corasaniti; Dale P Corkery; Nils Cordes; Katia Cortese; Maria do Carmo Costa; Sarah Costantino; Paola Costelli; Ana Coto-Montes; Peter J Crack; Jose L Crespo; Alfredo Criollo; Valeria Crippa; Riccardo Cristofani; Tamas Csizmadia; Antonio Cuadrado; Bing Cui; Jun Cui; Yixian Cui; Yong Cui; Emmanuel Culetto; Andrea C Cumino; Andrey V Cybulsky; Mark J Czaja; Stanislaw J Czuczwar; Stefania D'Adamo; Marcello D'Amelio; Daniela D'Arcangelo; Andrew C D'Lugos; Gabriella D'Orazi; James A da Silva; Hormos Salimi Dafsari; Ruben K Dagda; Yasin Dagdas; Maria Daglia; Xiaoxia Dai; Yun Dai; Yuyuan Dai; Jessica Dal Col; Paul Dalhaimer; Luisa Dalla Valle; Tobias Dallenga; Guillaume Dalmasso; Markus Damme; Ilaria Dando; Nico P Dantuma; April L Darling; Hiranmoy Das; Srinivasan Dasarathy; Santosh K Dasari; Srikanta Dash; Oliver Daumke; Adrian N Dauphinee; Jeffrey S Davies; Valeria A Dávila; Roger J Davis; Tanja Davis; Sharadha Dayalan Naidu; Francesca De Amicis; Karolien De Bosscher; Francesca De Felice; Lucia De Franceschi; Chiara De Leonibus; Mayara G de Mattos Barbosa; Guido R Y De Meyer; Angelo De Milito; Cosimo De Nunzio; Clara De Palma; Mauro De Santi; Claudio De Virgilio; Daniela De Zio; Jayanta Debnath; Brian J DeBosch; Jean-Paul Decuypere; Mark A Deehan; Gianluca Deflorian; James DeGregori; Benjamin Dehay; Gabriel Del Rio; Joe R Delaney; Lea M D Delbridge; Elizabeth Delorme-Axford; M Victoria Delpino; Francesca Demarchi; Vilma Dembitz; Nicholas D Demers; Hongbin Deng; Zhiqiang Deng; Joern Dengjel; Paul Dent; Donna Denton; Melvin L DePamphilis; Channing J Der; Vojo Deretic; Albert Descoteaux; Laura Devis; Sushil Devkota; Olivier Devuyst; Grant Dewson; Mahendiran Dharmasivam; Rohan Dhiman; Diego di Bernardo; Manlio Di Cristina; Fabio Di Domenico; Pietro Di Fazio; Alessio Di Fonzo; Giovanni Di Guardo; Gianni M Di Guglielmo; Luca Di Leo; Chiara Di Malta; Alessia Di Nardo; Martina Di Rienzo; Federica Di Sano; George Diallinas; Jiajie Diao; Guillermo Diaz-Araya; Inés Díaz-Laviada; Jared M Dickinson; Marc Diederich; Mélanie Dieudé; Ivan Dikic; Shiping Ding; Wen-Xing Ding; Luciana Dini; Jelena Dinić; Miroslav Dinic; Albena T Dinkova-Kostova; Marc S Dionne; Jörg H W Distler; Abhinav Diwan; Ian M C Dixon; Mojgan Djavaheri-Mergny; Ina Dobrinski; Oxana Dobrovinskaya; Radek Dobrowolski; Renwick C J Dobson; Jelena Đokić; Serap Dokmeci Emre; Massimo Donadelli; Bo Dong; Xiaonan Dong; Zhiwu Dong; Gerald W Dorn Ii; Volker Dotsch; Huan Dou; Juan Dou; Moataz Dowaidar; Sami Dridi; Liat Drucker; Ailian Du; Caigan Du; Guangwei Du; Hai-Ning Du; Li-Lin Du; André du Toit; Shao-Bin Duan; Xiaoqiong Duan; Sónia P Duarte; Anna Dubrovska; Elaine A Dunlop; Nicolas Dupont; Raúl V Durán; Bilikere S Dwarakanath; Sergey A Dyshlovoy; Darius Ebrahimi-Fakhari; Leopold Eckhart; Charles L Edelstein; Thomas Efferth; Eftekhar Eftekharpour; Ludwig Eichinger; Nabil Eid; Tobias Eisenberg; N Tony Eissa; Sanaa Eissa; Miriam Ejarque; Abdeljabar El Andaloussi; Nazira El-Hage; Shahenda El-Naggar; Anna Maria Eleuteri; Eman S El-Shafey; Mohamed Elgendy; Aristides G Eliopoulos; María M Elizalde; Philip M Elks; Hans-Peter Elsasser; Eslam S Elsherbiny; Brooke M Emerling; N C Tolga Emre; Christina H Eng; Nikolai Engedal; Anna-Mart Engelbrecht; Agnete S T Engelsen; Jorrit M Enserink; Ricardo Escalante; Audrey Esclatine; Mafalda Escobar-Henriques; Eeva-Liisa Eskelinen; Lucile Espert; Makandjou-Ola Eusebio; Gemma Fabrias; Cinzia Fabrizi; Antonio Facchiano; Francesco Facchiano; Bengt Fadeel; Claudio Fader; Alex C Faesen; W Douglas Fairlie; Alberto Falcó; Bjorn H Falkenburger; Daping Fan; Jie Fan; Yanbo Fan; Evandro F Fang; Yanshan Fang; Yognqi Fang; Manolis Fanto; Tamar Farfel-Becker; Mathias Faure; Gholamreza Fazeli; Anthony O Fedele; Arthur M Feldman; Du Feng; Jiachun Feng; Lifeng Feng; Yibin Feng; Yuchen Feng; Wei Feng; Thais Fenz Araujo; Thomas A Ferguson; Álvaro F Fernández; Jose C Fernandez-Checa; Sonia Fernández-Veledo; Alisdair R Fernie; Anthony W Ferrante; Alessandra Ferraresi; Merari F Ferrari; Julio C B Ferreira; Susan Ferro-Novick; Antonio Figueras; Riccardo Filadi; Nicoletta Filigheddu; Eduardo Filippi-Chiela; Giuseppe Filomeni; Gian Maria Fimia; Vittorio Fineschi; Francesca Finetti; Steven Finkbeiner; Edward A Fisher; Paul B Fisher; Flavio Flamigni; Steven J Fliesler; Trude H Flo; Ida Florance; Oliver Florey; Tullio Florio; Erika Fodor; Carlo Follo; Edward A Fon; Antonella Forlino; Francesco Fornai; Paola Fortini; Anna Fracassi; Alessandro Fraldi; Brunella Franco; Rodrigo Franco; Flavia Franconi; Lisa B Frankel; Scott L Friedman; Leopold F Fröhlich; Gema Frühbeck; Jose M Fuentes; Yukio Fujiki; Naonobu Fujita; Yuuki Fujiwara; Mitsunori Fukuda; Simone Fulda; Luc Furic; Norihiko Furuya; Carmela Fusco; Michaela U Gack; Lidia Gaffke; Sehamuddin Galadari; Alessia Galasso; Maria F Galindo; Sachith Gallolu Kankanamalage; Lorenzo Galluzzi; Vincent Galy; Noor Gammoh; Boyi Gan; Ian G Ganley; Feng Gao; Hui Gao; Minghui Gao; Ping Gao; Shou-Jiang Gao; Wentao Gao; Xiaobo Gao; Ana Garcera; Maria Noé Garcia; Verónica E Garcia; Francisco García-Del Portillo; Vega Garcia-Escudero; Aracely Garcia-Garcia; Marina Garcia-Macia; Diana García-Moreno; Carmen Garcia-Ruiz; Patricia García-Sanz; Abhishek D Garg; Ricardo Gargini; Tina Garofalo; Robert F Garry; Nils C Gassen; Damian Gatica; Liang Ge; Wanzhong Ge; Ruth Geiss-Friedlander; Cecilia Gelfi; Pascal Genschik; Ian E Gentle; Valeria Gerbino; Christoph Gerhardt; Kyla Germain; Marc Germain; David A Gewirtz; Elham Ghasemipour Afshar; Saeid Ghavami; Alessandra Ghigo; Manosij Ghosh; Georgios Giamas; Claudia Giampietri; Alexandra Giatromanolaki; Gary E Gibson; Spencer B Gibson; Vanessa Ginet; Edward Giniger; Carlotta Giorgi; Henrique Girao; Stephen E Girardin; Mridhula Giridharan; Sandy Giuliano; Cecilia Giulivi; Sylvie Giuriato; Julien Giustiniani; Alexander Gluschko; Veit Goder; Alexander Goginashvili; Jakub Golab; David C Goldstone; Anna Golebiewska; Luciana R Gomes; Rodrigo Gomez; Rubén Gómez-Sánchez; Maria Catalina Gomez-Puerto; Raquel Gomez-Sintes; Qingqiu Gong; Felix M Goni; Javier González-Gallego; Tomas Gonzalez-Hernandez; Rosa A Gonzalez-Polo; Jose A Gonzalez-Reyes; Patricia González-Rodríguez; Ing Swie Goping; Marina S Gorbatyuk; Nikolai V Gorbunov; Kıvanç Görgülü; Roxana M Gorojod; Sharon M Gorski; Sandro Goruppi; Cecilia Gotor; Roberta A Gottlieb; Illana Gozes; Devrim Gozuacik; Martin Graef; Markus H Gräler; Veronica Granatiero; Daniel Grasso; Joshua P Gray; Douglas R Green; Alexander Greenhough; Stephen L Gregory; Edward F Griffin; Mark W Grinstaff; Frederic Gros; Charles Grose; Angelina S Gross; Florian Gruber; Paolo Grumati; Tilman Grune; Xueyan Gu; Jun-Lin Guan; Carlos M Guardia; Kishore Guda; Flora Guerra; Consuelo Guerri; Prasun Guha; Carlos Guillén; Shashi Gujar; Anna Gukovskaya; Ilya Gukovsky; Jan Gunst; Andreas Günther; Anyonya R Guntur; Chuanyong Guo; Chun Guo; Hongqing Guo; Lian-Wang Guo; Ming Guo; Pawan Gupta; Shashi Kumar Gupta; Swapnil Gupta; Veer Bala Gupta; Vivek Gupta; Asa B Gustafsson; David D Gutterman; Ranjitha H B; Annakaisa Haapasalo; James E Haber; Aleksandra Hać; Shinji Hadano; Anders J Hafrén; Mansour Haidar; Belinda S Hall; Gunnel Halldén; Anne Hamacher-Brady; Andrea Hamann; Maho Hamasaki; Weidong Han; Malene Hansen; Phyllis I Hanson; Zijian Hao; Masaru Harada; Ljubica Harhaji-Trajkovic; Nirmala Hariharan; Nigil Haroon; James Harris; Takafumi Hasegawa; Noor Hasima Nagoor; Jeffrey A Haspel; Volker Haucke; Wayne D Hawkins; Bruce A Hay; Cole M Haynes; Soren B Hayrabedyan; Thomas S Hays; Congcong He; Qin He; Rong-Rong He; You-Wen He; Yu-Ying He; Yasser Heakal; Alexander M Heberle; J Fielding Hejtmancik; Gudmundur Vignir Helgason; Vanessa Henkel; Marc Herb; Alexander Hergovich; Anna Herman-Antosiewicz; Agustín Hernández; Carlos Hernandez; Sergio Hernandez-Diaz; Virginia Hernandez-Gea; Amaury Herpin; Judit Herreros; Javier H Hervás; Daniel Hesselson; Claudio Hetz; Volker T Heussler; Yujiro Higuchi; Sabine Hilfiker; Joseph A Hill; William S Hlavacek; Emmanuel A Ho; Idy H T Ho; Philip Wing-Lok Ho; Shu-Leong Ho; Wan Yun Ho; G Aaron Hobbs; Mark Hochstrasser; Peter H M Hoet; Daniel Hofius; Paul Hofman; Annika Höhn; Carina I Holmberg; Jose R Hombrebueno; Chang-Won Hong Yi-Ren Hong; Lora V Hooper; Thorsten Hoppe; Rastislav Horos; Yujin Hoshida; I-Lun Hsin; Hsin-Yun Hsu; Bing Hu; Dong Hu; Li-Fang Hu; Ming Chang Hu; Ronggui Hu; Wei Hu; Yu-Chen Hu; Zhuo-Wei Hu; Fang Hua; Jinlian Hua; Yingqi Hua; Chongmin Huan; Canhua Huang; Chuanshu Huang; Chuanxin Huang; Chunling Huang; Haishan Huang; Kun Huang; Michael L H Huang; Rui Huang; Shan Huang; Tianzhi Huang; Xing Huang; Yuxiang Jack Huang; Tobias B Huber; Virginie Hubert; Christian A Hubner; Stephanie M Hughes; William E Hughes; Magali Humbert; Gerhard Hummer; James H Hurley; Sabah Hussain; Salik Hussain; Patrick J Hussey; Martina Hutabarat; Hui-Yun Hwang; Seungmin Hwang; Antonio Ieni; Fumiyo Ikeda; Yusuke Imagawa; Yuzuru Imai; Carol Imbriano; Masaya Imoto; Denise M Inman; Ken Inoki; Juan Iovanna; Renato V Iozzo; Giuseppe Ippolito; Javier E Irazoqui; Pablo Iribarren; Mohd Ishaq; Makoto Ishikawa; Nestor Ishimwe; Ciro Isidoro; Nahed Ismail; Shohreh Issazadeh-Navikas; Eisuke Itakura; Daisuke Ito; Davor Ivankovic; Saška Ivanova; Anand Krishnan V Iyer; José M Izquierdo; Masanori Izumi; Marja Jäättelä; Majid Sakhi Jabir; William T Jackson; Nadia Jacobo-Herrera; Anne-Claire Jacomin; Elise Jacquin; Pooja Jadiya; Hartmut Jaeschke; Chinnaswamy Jagannath; Arjen J Jakobi; Johan Jakobsson; Bassam Janji; Pidder Jansen-Dürr; Patric J Jansson; Jonathan Jantsch; Sławomir Januszewski; Alagie Jassey; Steve Jean; Hélène Jeltsch-David; Pavla Jendelova; Andreas Jenny; Thomas E Jensen; Niels Jessen; Jenna L Jewell; Jing Ji; Lijun Jia; Rui Jia; Liwen Jiang; Qing Jiang; Richeng Jiang; Teng Jiang; Xuejun Jiang; Yu Jiang; Maria Jimenez-Sanchez; Eun-Jung Jin; Fengyan Jin; Hongchuan Jin; Li Jin; Luqi Jin; Meiyan Jin; Si Jin; Eun-Kyeong Jo; Carine Joffre; Terje Johansen; Gail V W Johnson; Simon A Johnston; Eija Jokitalo; Mohit Kumar Jolly; Leo A B Joosten; Joaquin Jordan; Bertrand Joseph; Dianwen Ju; Jeong-Sun Ju; Jingfang Ju; Esmeralda Juárez; Delphine Judith; Gábor Juhász; Youngsoo Jun; Chang Hwa Jung; Sung-Chul Jung; Yong Keun Jung; Heinz Jungbluth; Johannes Jungverdorben; Steffen Just; Kai Kaarniranta; Allen Kaasik; Tomohiro Kabuta; Daniel Kaganovich; Alon Kahana; Renate Kain; Shinjo Kajimura; Maria Kalamvoki; Manjula Kalia; Danuta S Kalinowski; Nina Kaludercic; Ioanna Kalvari; Joanna Kaminska; Vitaliy O Kaminskyy; Hiromitsu Kanamori; Keizo Kanasaki; Chanhee Kang; Rui Kang; Sang Sun Kang; Senthilvelrajan Kaniyappan; Tomotake Kanki; Thirumala-Devi Kanneganti; Anumantha G Kanthasamy; Arthi Kanthasamy; Marc Kantorow; Orsolya Kapuy; Michalis V Karamouzis; Md Razaul Karim; Parimal Karmakar; Rajesh G Katare; Masaru Kato; Stefan H E Kaufmann; Anu Kauppinen; Gur P Kaushal; Susmita Kaushik; Kiyoshi Kawasaki; Kemal Kazan; Po-Yuan Ke; Damien J Keating; Ursula Keber; John H Kehrl; Kate E Keller; Christian W Keller; Jongsook Kim Kemper; Candia M Kenific; Oliver Kepp; Stephanie Kermorgant; Andreas Kern; Robin Ketteler; Tom G Keulers; Boris Khalfin; Hany Khalil; Bilon Khambu; Shahid Y Khan; Vinoth Kumar Megraj Khandelwal; Rekha Khandia; Widuri Kho; Noopur V Khobrekar; Sataree Khuansuwan; Mukhran Khundadze; Samuel A Killackey; Dasol Kim; Deok Ryong Kim; Do-Hyung Kim; Dong-Eun Kim; Eun Young Kim; Eun-Kyoung Kim; Hak-Rim Kim; Hee-Sik Kim; Jeong Hun Kim; Jin Kyung Kim; Jin-Hoi Kim; Joungmok Kim; Ju Hwan Kim; Keun Il Kim; Peter K Kim; Seong-Jun Kim; Scot R Kimball; Adi Kimchi; Alec C Kimmelman; Tomonori Kimura; Matthew A King; Kerri J Kinghorn; Conan G Kinsey; Vladimir Kirkin; Lorrie A Kirshenbaum; Sergey L Kiselev; Shuji Kishi; Katsuhiko Kitamoto; Yasushi Kitaoka; Kaio Kitazato; Richard N Kitsis; Josef T Kittler; Ole Kjaerulff; Peter S Klein; Thomas Klopstock; Jochen Klucken; Helene Knævelsrud; Roland L Knorr; Ben C B Ko; Fred Ko; Jiunn-Liang Ko; Hotaka Kobayashi; Satoru Kobayashi; Ina Koch; Jan C Koch; Ulrich Koenig; Donat Kögel; Young Ho Koh; Masato Koike; Sepp D Kohlwein; Nur M Kocaturk; Masaaki Komatsu; Jeannette König; Toru Kono; Benjamin T Kopp; Tamas Korcsmaros; Gözde Korkmaz; Viktor I Korolchuk; Mónica Suárez Korsnes; Ali Koskela; Janaiah Kota; Yaichiro Kotake; Monica L Kotler; Yanjun Kou; Michael I Koukourakis; Evangelos Koustas; Attila L Kovacs; Tibor Kovács; Daisuke Koya; Tomohiro Kozako; Claudine Kraft; Dimitri Krainc; Helmut Krämer; Anna D Krasnodembskaya; Carole Kretz-Remy; Guido Kroemer; Nicholas T Ktistakis; Kazuyuki Kuchitsu; Sabine Kuenen; Lars Kuerschner; Thomas Kukar; Ajay Kumar; Ashok Kumar; Deepak Kumar; Dhiraj Kumar; Sharad Kumar; Shinji Kume; Caroline Kumsta; Chanakya N Kundu; Mondira Kundu; Ajaikumar B Kunnumakkara; Lukasz Kurgan; Tatiana G Kutateladze; Ozlem Kutlu; SeongAe Kwak; Ho Jeong Kwon; Taeg Kyu Kwon; Yong Tae Kwon; Irene Kyrmizi; Albert La Spada; Patrick Labonté; Sylvain Ladoire; Ilaria Laface; Frank Lafont; Diane C Lagace; Vikramjit Lahiri; Zhibing Lai; Angela S Laird; Aparna Lakkaraju; Trond Lamark; Sheng-Hui Lan; Ane Landajuela; Darius J R Lane; Jon D Lane; Charles H Lang; Carsten Lange; Ülo Langel; Rupert Langer; Pierre Lapaquette; Jocelyn Laporte; Nicholas F LaRusso; Isabel Lastres-Becker; Wilson Chun Yu Lau; Gordon W Laurie; Sergio Lavandero; Betty Yuen Kwan Law; Helen Ka-Wai Law; Rob Layfield; Weidong Le; Herve Le Stunff; Alexandre Y Leary; Jean-Jacques Lebrun; Lionel Y W Leck; Jean-Philippe Leduc-Gaudet; Changwook Lee; Chung-Pei Lee; Da-Hye Lee; Edward B Lee; Erinna F Lee; Gyun Min Lee; He-Jin Lee; Heung Kyu Lee; Jae Man Lee; Jason S Lee; Jin-A Lee; Joo-Yong Lee; Jun Hee Lee; Michael Lee; Min Goo Lee; Min Jae Lee; Myung-Shik Lee; Sang Yoon Lee; Seung-Jae Lee; Stella Y Lee; Sung Bae Lee; Won Hee Lee; Ying-Ray Lee; Yong-Ho Lee; Youngil Lee; Christophe Lefebvre; Renaud Legouis; Yu L Lei; Yuchen Lei; Sergey Leikin; Gerd Leitinger; Leticia Lemus; Shuilong Leng; Olivia Lenoir; Guido Lenz; Heinz Josef Lenz; Paola Lenzi; Yolanda León; Andréia M Leopoldino; Christoph Leschczyk; Stina Leskelä; Elisabeth Letellier; Chi-Ting Leung; Po Sing Leung; Jeremy S Leventhal; Beth Levine; Patrick A Lewis; Klaus Ley; Bin Li; Da-Qiang Li; Jianming Li; Jing Li; Jiong Li; Ke Li; Liwu Li; Mei Li; Min Li; Min Li; Ming Li; Mingchuan Li; Pin-Lan Li; Ming-Qing Li; Qing Li; Sheng Li; Tiangang Li; Wei Li; Wenming Li; Xue Li; Yi-Ping Li; Yuan Li; Zhiqiang Li; Zhiyong Li; Zhiyuan Li; Jiqin Lian; Chengyu Liang; Qiangrong Liang; Weicheng Liang; Yongheng Liang; YongTian Liang; Guanghong Liao; Lujian Liao; Mingzhi Liao; Yung-Feng Liao; Mariangela Librizzi; Pearl P Y Lie; Mary A Lilly; Hyunjung J Lim; Thania R R Lima; Federica Limana; Chao Lin; Chih-Wen Lin; Dar-Shong Lin; Fu-Cheng Lin; Jiandie D Lin; Kurt M Lin; Kwang-Huei Lin; Liang-Tzung Lin; Pei-Hui Lin; Qiong Lin; Shaofeng Lin; Su-Ju Lin; Wenyu Lin; Xueying Lin; Yao-Xin Lin; Yee-Shin Lin; Rafael Linden; Paula Lindner; Shuo-Chien Ling; Paul Lingor; Amelia K Linnemann; Yih-Cherng Liou; Marta M Lipinski; Saška Lipovšek; Vitor A Lira; Natalia Lisiak; Paloma B Liton; Chao Liu; Ching-Hsuan Liu; Chun-Feng Liu; Cui Hua Liu; Fang Liu; Hao Liu; Hsiao-Sheng Liu; Hua-Feng Liu; Huifang Liu; Jia Liu; Jing Liu; Julia Liu; Leyuan Liu; Longhua Liu; Meilian Liu; Qin Liu; Wei Liu; Wende Liu; Xiao-Hong Liu; Xiaodong Liu; Xingguo Liu; Xu Liu; Xuedong Liu; Yanfen Liu; Yang Liu; Yang Liu; Yueyang Liu; Yule Liu; J Andrew Livingston; Gerard Lizard; Jose M Lizcano; Senka Ljubojevic-Holzer; Matilde E LLeonart; David Llobet-Navàs; Alicia Llorente; Chih Hung Lo; Damián Lobato-Márquez; Qi Long; Yun Chau Long; Ben Loos; Julia A Loos; Manuela G López; Guillermo López-Doménech; José Antonio López-Guerrero; Ana T López-Jiménez; Óscar López-Pérez; Israel López-Valero; Magdalena J Lorenowicz; Mar Lorente; Peter Lorincz; Laura Lossi; Sophie Lotersztajn; Penny E Lovat; Jonathan F Lovell; Alenka Lovy; Péter Lőw; Guang Lu; Haocheng Lu; Jia-Hong Lu; Jin-Jian Lu; Mengji Lu; Shuyan Lu; Alessandro Luciani; John M Lucocq; Paula Ludovico; Micah A Luftig; Morten Luhr; Diego Luis-Ravelo; Julian J Lum; Liany Luna-Dulcey; Anders H Lund; Viktor K Lund; Jan D Lünemann; Patrick Lüningschrör; Honglin Luo; Rongcan Luo; Shouqing Luo; Zhi Luo; Claudio Luparello; Bernhard Lüscher; Luan Luu; Alex Lyakhovich; Konstantin G Lyamzaev; Alf Håkon Lystad; Lyubomyr Lytvynchuk; Alvin C Ma; Changle Ma; Mengxiao Ma; Ning-Fang Ma; Quan-Hong Ma; Xinliang Ma; Yueyun Ma; Zhenyi Ma; Ormond A MacDougald; Fernando Macian; Gustavo C MacIntosh; Jeffrey P MacKeigan; Kay F Macleod; Sandra Maday; Frank Madeo; Muniswamy Madesh; Tobias Madl; Julio Madrigal-Matute; Akiko Maeda; Yasuhiro Maejima; Marta Magarinos; Poornima Mahavadi; Emiliano Maiani; Kenneth Maiese; Panchanan Maiti; Maria Chiara Maiuri; Barbara Majello; Michael B Major; Elena Makareeva; Fayaz Malik; Karthik Mallilankaraman; Walter Malorni; Alina Maloyan; Najiba Mammadova; Gene Chi Wai Man; Federico Manai; Joseph D Mancias; Eva-Maria Mandelkow; Michael A Mandell; Angelo A Manfredi; Masoud H Manjili; Ravi Manjithaya; Patricio Manque; Bella B Manshian; Raquel Manzano; Claudia Manzoni; Kai Mao; Cinzia Marchese; Sandrine Marchetti; Anna Maria Marconi; Fabrizio Marcucci; Stefania Mardente; Olga A Mareninova; Marta Margeta; Muriel Mari; Sara Marinelli; Oliviero Marinelli; Guillermo Mariño; Sofia Mariotto; Richard S Marshall; Mark R Marten; Sascha Martens; Alexandre P J Martin; Katie R Martin; Sara Martin; Shaun Martin; Adrián Martín-Segura; Miguel A Martín-Acebes; Inmaculada Martin-Burriel; Marcos Martin-Rincon; Paloma Martin-Sanz; José A Martina; Wim Martinet; Aitor Martinez; Ana Martinez; Jennifer Martinez; Moises Martinez Velazquez; Nuria Martinez-Lopez; Marta Martinez-Vicente; Daniel O Martins; Joilson O Martins; Waleska K Martins; Tania Martins-Marques; Emanuele Marzetti; Shashank Masaldan; Celine Masclaux-Daubresse; Douglas G Mashek; Valentina Massa; Lourdes Massieu; Glenn R Masson; Laura Masuelli; Anatoliy I Masyuk; Tetyana V Masyuk; Paola Matarrese; Ander Matheu; Satoaki Matoba; Sachiko Matsuzaki; Pamela Mattar; Alessandro Matte; Domenico Mattoscio; José L Mauriz; Mario Mauthe; Caroline Mauvezin; Emanual Maverakis; Paola Maycotte; Johanna Mayer; Gianluigi Mazzoccoli; Cristina Mazzoni; Joseph R Mazzulli; Nami McCarty; Christine McDonald; Mitchell R McGill; Sharon L McKenna; BethAnn McLaughlin; Fionn McLoughlin; Mark A McNiven; Thomas G McWilliams; Fatima Mechta-Grigoriou; Tania Catarina Medeiros; Diego L Medina; Lynn A Megeney; Klara Megyeri; Maryam Mehrpour; Jawahar L Mehta; Alfred J Meijer; Annemarie H Meijer; Jakob Mejlvang; Alicia Meléndez; Annette Melk; Gonen Memisoglu; Alexandrina F Mendes; Delong Meng; Fei Meng; Tian Meng; Rubem Menna-Barreto; Manoj B Menon; Carol Mercer; Anne E Mercier; Jean-Louis Mergny; Adalberto Merighi; Seth D Merkley; Giuseppe Merla; Volker Meske; Ana Cecilia Mestre; Shree Padma Metur; Christian Meyer; Hemmo Meyer; Wenyi Mi; Jeanne Mialet-Perez; Junying Miao; Lucia Micale; Yasuo Miki; Enrico Milan; Małgorzata Milczarek; Dana L Miller; Samuel I Miller; Silke Miller; Steven W Millward; Ira Milosevic; Elena A Minina; Hamed Mirzaei; Hamid Reza Mirzaei; Mehdi Mirzaei; Amit Mishra; Nandita Mishra; Paras Kumar Mishra; Maja Misirkic Marjanovic; Roberta Misasi; Amit Misra; Gabriella Misso; Claire Mitchell; Geraldine Mitou; Tetsuji Miura; Shigeki Miyamoto; Makoto Miyazaki; Mitsunori Miyazaki; Taiga Miyazaki; Keisuke Miyazawa; Noboru Mizushima; Trine H Mogensen; Baharia Mograbi; Reza Mohammadinejad; Yasir Mohamud; Abhishek Mohanty; Sipra Mohapatra; Torsten Möhlmann; Asif Mohmmed; Anna Moles; Kelle H Moley; Maurizio Molinari; Vincenzo Mollace; Andreas Buch Møller; Bertrand Mollereau; Faustino Mollinedo; Costanza Montagna; Mervyn J Monteiro; Andrea Montella; L Ruth Montes; Barbara Montico; Vinod K Mony; Giacomo Monzio Compagnoni; Michael N Moore; Mohammad A Moosavi; Ana L Mora; Marina Mora; David Morales-Alamo; Rosario Moratalla; Paula I Moreira; Elena Morelli; Sandra Moreno; Daniel Moreno-Blas; Viviana Moresi; Benjamin Morga; Alwena H Morgan; Fabrice Morin; Hideaki Morishita; Orson L Moritz; Mariko Moriyama; Yuji Moriyasu; Manuela Morleo; Eugenia Morselli; Jose F Moruno-Manchon; Jorge Moscat; Serge Mostowy; Elisa Motori; Andrea Felinto Moura; Naima Moustaid-Moussa; Maria Mrakovcic; Gabriel Muciño-Hernández; Anupam Mukherjee; Subhadip Mukhopadhyay; Jean M Mulcahy Levy; Victoriano Mulero; Sylviane Muller; Christian Münch; Ashok Munjal; Pura Munoz-Canoves; Teresa Muñoz-Galdeano; Christian Münz; Tomokazu Murakawa; Claudia Muratori; Brona M Murphy; J Patrick Murphy; Aditya Murthy; Timo T Myöhänen; Indira U Mysorekar; Jennifer Mytych; Seyed Mohammad Nabavi; Massimo Nabissi; Péter Nagy; Jihoon Nah; Aimable Nahimana; Ichiro Nakagawa; Ken Nakamura; Hitoshi Nakatogawa; Shyam S Nandi; Meera Nanjundan; Monica Nanni; Gennaro Napolitano; Roberta Nardacci; Masashi Narita; Melissa Nassif; Ilana Nathan; Manabu Natsumeda; Ryno J Naude; Christin Naumann; Olaia Naveiras; Fatemeh Navid; Steffan T Nawrocki; Taras Y Nazarko; Francesca Nazio; Florentina Negoita; Thomas Neill; Amanda L Neisch; Luca M Neri; Mihai G Netea; Patrick Neubert; Thomas P Neufeld; Dietbert Neumann; Albert Neutzner; Phillip T Newton; Paul A Ney; Ioannis P Nezis; Charlene C W Ng; Tzi Bun Ng; Hang T T Nguyen; Long T Nguyen; Hong-Min Ni; Clíona Ní Cheallaigh; Zhenhong Ni; M Celeste Nicolao; Francesco Nicoli; Manuel Nieto-Diaz; Per Nilsson; Shunbin Ning; Rituraj Niranjan; Hiroshi Nishimune; Mireia Niso-Santano; Ralph A Nixon; Annalisa Nobili; Clevio Nobrega; Takeshi Noda; Uxía Nogueira-Recalde; Trevor M Nolan; Ivan Nombela; Ivana Novak; Beatriz Novoa; Takashi Nozawa; Nobuyuki Nukina; Carmen Nussbaum-Krammer; Jesper Nylandsted; Tracey R O'Donovan; Seónadh M O'Leary; Eyleen J O'Rourke; Mary P O'Sullivan; Timothy E O'Sullivan; Salvatore Oddo; Ina Oehme; Michinaga Ogawa; Eric Ogier-Denis; Margret H Ogmundsdottir; Besim Ogretmen; Goo Taeg Oh; Seon-Hee Oh; Young J Oh; Takashi Ohama; Yohei Ohashi; Masaki Ohmuraya; Vasileios Oikonomou; Rani Ojha; Koji Okamoto; Hitoshi Okazawa; Masahide Oku; Sara Oliván; Jorge M A Oliveira; Michael Ollmann; James A Olzmann; Shakib Omari; M Bishr Omary; Gizem Önal; Martin Ondrej; Sang-Bing Ong; Sang-Ging Ong; Anna Onnis; Juan A Orellana; Sara Orellana-Muñoz; Maria Del Mar Ortega-Villaizan; Xilma R Ortiz-Gonzalez; Elena Ortona; Heinz D Osiewacz; Abdel-Hamid K Osman; Rosario Osta; Marisa S Otegui; Kinya Otsu; Christiane Ott; Luisa Ottobrini; Jing-Hsiung James Ou; Tiago F Outeiro; Inger Oynebraten; Melek Ozturk; Gilles Pagès; Susanta Pahari; Marta Pajares; Utpal B Pajvani; Rituraj Pal; Simona Paladino; Nicolas Pallet; Michela Palmieri; Giuseppe Palmisano; Camilla Palumbo; Francesco Pampaloni; Lifeng Pan; Qingjun Pan; Wenliang Pan; Xin Pan; Ganna Panasyuk; Rahul Pandey; Udai B Pandey; Vrajesh Pandya; Francesco Paneni; Shirley Y Pang; Elisa Panzarini; Daniela L Papademetrio; Elena Papaleo; Daniel Papinski; Diana Papp; Eun Chan Park; Hwan Tae Park; Ji-Man Park; Jong-In Park; Joon Tae Park; Junsoo Park; Sang Chul Park; Sang-Youel Park; Abraham H Parola; Jan B Parys; Adrien Pasquier; Benoit Pasquier; João F Passos; Nunzia Pastore; Hemal H Patel; Daniel Patschan; Sophie Pattingre; Gustavo Pedraza-Alva; Jose Pedraza-Chaverri; Zully Pedrozo; Gang Pei; Jianming Pei; Hadas Peled-Zehavi; Joaquín M Pellegrini; Joffrey Pelletier; Miguel A Peñalva; Di Peng; Ying Peng; Fabio Penna; Maria Pennuto; Francesca Pentimalli; Cláudia Mf Pereira; Gustavo J S Pereira; Lilian C Pereira; Luis Pereira de Almeida; Nirma D Perera; Ángel Pérez-Lara; Ana B Perez-Oliva; María Esther Pérez-Pérez; Palsamy Periyasamy; Andras Perl; Cristiana Perrotta; Ida Perrotta; Richard G Pestell; Morten Petersen; Irina Petrache; Goran Petrovski; Thorsten Pfirrmann; Astrid S Pfister; Jennifer A Philips; Huifeng Pi; Anna Picca; Alicia M Pickrell; Sandy Picot; Giovanna M Pierantoni; Marina Pierdominici; Philippe Pierre; Valérie Pierrefite-Carle; Karolina Pierzynowska; Federico Pietrocola; Miroslawa Pietruczuk; Claudio Pignata; Felipe X Pimentel-Muiños; Mario Pinar; Roberta O Pinheiro; Ronit Pinkas-Kramarski; Paolo Pinton; Karolina Pircs; Sujan Piya; Paola Pizzo; Theo S Plantinga; Harald W Platta; Ainhoa Plaza-Zabala; Markus Plomann; Egor Y Plotnikov; Helene Plun-Favreau; Ryszard Pluta; Roger Pocock; Stefanie Pöggeler; Christian Pohl; Marc Poirot; Angelo Poletti; Marisa Ponpuak; Hana Popelka; Blagovesta Popova; Helena Porta; Soledad Porte Alcon; Eliana Portilla-Fernandez; Martin Post; Malia B Potts; Joanna Poulton; Ted Powers; Veena Prahlad; Tomasz K Prajsnar; Domenico Praticò; Rosaria Prencipe; Muriel Priault; Tassula Proikas-Cezanne; Vasilis J Promponas; Christopher G Proud; Rosa Puertollano; Luigi Puglielli; Thomas Pulinilkunnil; Deepika Puri; Rajat Puri; Julien Puyal; Xiaopeng Qi; Yongmei Qi; Wenbin Qian; Lei Qiang; Yu Qiu; Joe Quadrilatero; Jorge Quarleri; Nina Raben; Hannah Rabinowich; Debora Ragona; Michael J Ragusa; Nader Rahimi; Marveh Rahmati; Valeria Raia; Nuno Raimundo; Namakkal-Soorappan Rajasekaran; Sriganesh Ramachandra Rao; Abdelhaq Rami; Ignacio Ramírez-Pardo; David B Ramsden; Felix Randow; Pundi N Rangarajan; Danilo Ranieri; Hai Rao; Lang Rao; Rekha Rao; Sumit Rathore; J Arjuna Ratnayaka; Edward A Ratovitski; Palaniyandi Ravanan; Gloria Ravegnini; Swapan K Ray; Babak Razani; Vito Rebecca; Fulvio Reggiori; Anne Régnier-Vigouroux; Andreas S Reichert; David Reigada; Jan H Reiling; Theo Rein; Siegfried Reipert; Rokeya Sultana Rekha; Hongmei Ren; Jun Ren; Weichao Ren; Tristan Renault; Giorgia Renga; Karen Reue; Kim Rewitz; Bruna Ribeiro de Andrade Ramos; S Amer Riazuddin; Teresa M Ribeiro-Rodrigues; Jean-Ehrland Ricci; Romeo Ricci; Victoria Riccio; Des R Richardson; Yasuko Rikihisa; Makarand V Risbud; Ruth M Risueño; Konstantinos Ritis; Salvatore Rizza; Rosario Rizzuto; Helen C Roberts; Luke D Roberts; Katherine J Robinson; Maria Carmela Roccheri; Stephane Rocchi; George G Rodney; Tiago Rodrigues; Vagner Ramon Rodrigues Silva; Amaia Rodriguez; Ruth Rodriguez-Barrueco; Nieves Rodriguez-Henche; Humberto Rodriguez-Rocha; Jeroen Roelofs; Robert S Rogers; Vladimir V Rogov; Ana I Rojo; Krzysztof Rolka; Vanina Romanello; Luigina Romani; Alessandra Romano; Patricia S Romano; David Romeo-Guitart; Luis C Romero; Montserrat Romero; Joseph C Roney; Christopher Rongo; Sante Roperto; Mathias T Rosenfeldt; Philip Rosenstiel; Anne G Rosenwald; Kevin A Roth; Lynn Roth; Steven Roth; Kasper M A Rouschop; Benoit D Roussel; Sophie Roux; Patrizia Rovere-Querini; Ajit Roy; Aurore Rozieres; Diego Ruano; David C Rubinsztein; Maria P Rubtsova; Klaus Ruckdeschel; Christoph Ruckenstuhl; Emil Rudolf; Rüdiger Rudolf; Alessandra Ruggieri; Avnika Ashok Ruparelia; Paola Rusmini; Ryan R Russell; Gian Luigi Russo; Maria Russo; Rossella Russo; Oxana O Ryabaya; Kevin M Ryan; Kwon-Yul Ryu; Maria Sabater-Arcis; Ulka Sachdev; Michael Sacher; Carsten Sachse; Abhishek Sadhu; Junichi Sadoshima; Nathaniel Safren; Paul Saftig; Antonia P Sagona; Gaurav Sahay; Amirhossein Sahebkar; Mustafa Sahin; Ozgur Sahin; Sumit Sahni; Nayuta Saito; Shigeru Saito; Tsunenori Saito; Ryohei Sakai; Yasuyoshi Sakai; Jun-Ichi Sakamaki; Kalle Saksela; Gloria Salazar; Anna Salazar-Degracia; Ghasem H Salekdeh; Ashok K Saluja; Belém Sampaio-Marques; Maria Cecilia Sanchez; Jose A Sanchez-Alcazar; Victoria Sanchez-Vera; Vanessa Sancho-Shimizu; J Thomas Sanderson; Marco Sandri; Stefano Santaguida; Laura Santambrogio; Magda M Santana; Giorgio Santoni; Alberto Sanz; Pascual Sanz; Shweta Saran; Marco Sardiello; Timothy J Sargeant; Apurva Sarin; Chinmoy Sarkar; Sovan Sarkar; Maria-Rosa Sarrias; Surajit Sarkar; Dipanka Tanu Sarmah; Jaakko Sarparanta; Aishwarya Sathyanarayan; Ranganayaki Sathyanarayanan; K Matthew Scaglione; Francesca Scatozza; Liliana Schaefer; Zachary T Schafer; Ulrich E Schaible; Anthony H V Schapira; Michael Scharl; Hermann M Schatzl; Catherine H Schein; Wiep Scheper; David Scheuring; Maria Vittoria Schiaffino; Monica Schiappacassi; Rainer Schindl; Uwe Schlattner; Oliver Schmidt; Roland Schmitt; Stephen D Schmidt; Ingo Schmitz; Eran Schmukler; Anja Schneider; Bianca E Schneider; Romana Schober; Alejandra C Schoijet; Micah B Schott; Michael Schramm; Bernd Schröder; Kai Schuh; Christoph Schüller; Ryan J Schulze; Lea Schürmanns; Jens C Schwamborn; Melanie Schwarten; Filippo Scialo; Sebastiano Sciarretta; Melanie J Scott; Kathleen W Scotto; A Ivana Scovassi; Andrea Scrima; Aurora Scrivo; David Sebastian; Salwa Sebti; Simon Sedej; Laura Segatori; Nava Segev; Per O Seglen; Iban Seiliez; Ekihiro Seki; Scott B Selleck; Frank W Sellke; Joshua T Selsby; Michael Sendtner; Serif Senturk; Elena Seranova; Consolato Sergi; Ruth Serra-Moreno; Hiromi Sesaki; Carmine Settembre; Subba Rao Gangi Setty; Gianluca Sgarbi; Ou Sha; John J Shacka; Javeed A Shah; Dantong Shang; Changshun Shao; Feng Shao; Soroush Sharbati; Lisa M Sharkey; Dipali Sharma; Gaurav Sharma; Kulbhushan Sharma; Pawan Sharma; Surendra Sharma; Han-Ming Shen; Hongtao Shen; Jiangang Shen; Ming Shen; Weili Shen; Zheni Shen; Rui Sheng; Zhi Sheng; Zu-Hang Sheng; Jianjian Shi; Xiaobing Shi; Ying-Hong Shi; Kahori Shiba-Fukushima; Jeng-Jer Shieh; Yohta Shimada; Shigeomi Shimizu; Makoto Shimozawa; Takahiro Shintani; Christopher J Shoemaker; Shahla Shojaei; Ikuo Shoji; Bhupendra V Shravage; Viji Shridhar; Chih-Wen Shu; Hong-Bing Shu; Ke Shui; Arvind K Shukla; Timothy E Shutt; Valentina Sica; Aleem Siddiqui; Amanda Sierra; Virginia Sierra-Torre; Santiago Signorelli; Payel Sil; Bruno J de Andrade Silva; Johnatas D Silva; Eduardo Silva-Pavez; Sandrine Silvente-Poirot; Rachel E Simmonds; Anna Katharina Simon; Hans-Uwe Simon; Matias Simons; Anurag Singh; Lalit P Singh; Rajat Singh; Shivendra V Singh; Shrawan K Singh; Sudha B Singh; Sunaina Singh; Surinder Pal Singh; Debasish Sinha; Rohit Anthony Sinha; Sangita Sinha; Agnieszka Sirko; Kapil Sirohi; Efthimios L Sivridis; Panagiotis Skendros; Aleksandra Skirycz; Iva Slaninová; Soraya S Smaili; Andrei Smertenko; Matthew D Smith; Stefaan J Soenen; Eun Jung Sohn; Sophia P M Sok; Giancarlo Solaini; Thierry Soldati; Scott A Soleimanpour; Rosa M Soler; Alexei Solovchenko; Jason A Somarelli; Avinash Sonawane; Fuyong Song; Hyun Kyu Song; Ju-Xian Song; Kunhua Song; Zhiyin Song; Leandro R Soria; Maurizio Sorice; Alexander A Soukas; Sandra-Fausia Soukup; Diana Sousa; Nadia Sousa; Paul A Spagnuolo; Stephen A Spector; M M Srinivas Bharath; Daret St Clair; Venturina Stagni; Leopoldo Staiano; Clint A Stalnecker; Metodi V Stankov; Peter B Stathopulos; Katja Stefan; Sven Marcel Stefan; Leonidas Stefanis; Joan S Steffan; Alexander Steinkasserer; Harald Stenmark; Jared Sterneckert; Craig Stevens; Veronika Stoka; Stephan Storch; Björn Stork; Flavie Strappazzon; Anne Marie Strohecker; Dwayne G Stupack; Huanxing Su; Ling-Yan Su; Longxiang Su; Ana M Suarez-Fontes; Carlos S Subauste; Selvakumar Subbian; Paula V Subirada; Ganapasam Sudhandiran; Carolyn M Sue; Xinbing Sui; Corey Summers; Guangchao Sun; Jun Sun; Kang Sun; Meng-Xiang Sun; Qiming Sun; Yi Sun; Zhongjie Sun; Karen K S Sunahara; Eva Sundberg; Katalin Susztak; Peter Sutovsky; Hidekazu Suzuki; Gary Sweeney; J David Symons; Stephen Cho Wing Sze; Nathaniel J Szewczyk; Anna Tabęcka-Łonczynska; Claudio Tabolacci; Frank Tacke; Heinrich Taegtmeyer; Marco Tafani; Mitsuo Tagaya; Haoran Tai; Stephen W G Tait; Yoshinori Takahashi; Szabolcs Takats; Priti Talwar; Chit Tam; Shing Yau Tam; Davide Tampellini; Atsushi Tamura; Chong Teik Tan; Eng-King Tan; Ya-Qin Tan; Masaki Tanaka; Motomasa Tanaka; Daolin Tang; Jingfeng Tang; Tie-Shan Tang; Isei Tanida; Zhipeng Tao; Mohammed Taouis; Lars Tatenhorst; Nektarios Tavernarakis; Allen Taylor; Gregory A Taylor; Joan M Taylor; Elena Tchetina; Andrew R Tee; Irmgard Tegeder; David Teis; Natercia Teixeira; Fatima Teixeira-Clerc; Kumsal A Tekirdag; Tewin Tencomnao; Sandra Tenreiro; Alexei V Tepikin; Pilar S Testillano; Gianluca Tettamanti; Pierre-Louis Tharaux; Kathrin Thedieck; Arvind A Thekkinghat; Stefano Thellung; Josephine W Thinwa; V P Thirumalaikumar; Sufi Mary Thomas; Paul G Thomes; Andrew Thorburn; Lipi Thukral; Thomas Thum; Michael Thumm; Ling Tian; Ales Tichy; Andreas Till; Vincent Timmerman; Vladimir I Titorenko; Sokol V Todi; Krassimira Todorova; Janne M Toivonen; Luana Tomaipitinca; Dhanendra Tomar; Cristina Tomas-Zapico; Sergej Tomić; Benjamin Chun-Kit Tong; Chao Tong; Xin Tong; Sharon A Tooze; Maria L Torgersen; Satoru Torii; Liliana Torres-López; Alicia Torriglia; Christina G Towers; Roberto Towns; Shinya Toyokuni; Vladimir Trajkovic; Donatella Tramontano; Quynh-Giao Tran; Leonardo H Travassos; Charles B Trelford; Shirley Tremel; Ioannis P Trougakos; Betty P Tsao; Mario P Tschan; Hung-Fat Tse; Tak Fu Tse; Hitoshi Tsugawa; Andrey S Tsvetkov; David A Tumbarello; Yasin Tumtas; María J Tuñón; Sandra Turcotte; Boris Turk; Vito Turk; Bradley J Turner; Richard I Tuxworth; Jessica K Tyler; Elena V Tyutereva; Yasuo Uchiyama; Aslihan Ugun-Klusek; Holm H Uhlig; Marzena Ułamek-Kozioł; Ilya V Ulasov; Midori Umekawa; Christian Ungermann; Rei Unno; Sylvie Urbe; Elisabet Uribe-Carretero; Suayib Üstün; Vladimir N Uversky; Thomas Vaccari; Maria I Vaccaro; Björn F Vahsen; Helin Vakifahmetoglu-Norberg; Rut Valdor; Maria J Valente; Ayelén Valko; Richard B Vallee; Angela M Valverde; Greet Van den Berghe; Stijn van der Veen; Luc Van Kaer; Jorg van Loosdregt; Sjoerd J L van Wijk; Wim Vandenberghe; Ilse Vanhorebeek; Marcos A Vannier-Santos; Nicola Vannini; M Cristina Vanrell; Chiara Vantaggiato; Gabriele Varano; Isabel Varela-Nieto; Máté Varga; M Helena Vasconcelos; Somya Vats; Demetrios G Vavvas; Ignacio Vega-Naredo; Silvia Vega-Rubin-de-Celis; Guillermo Velasco; Ariadna P Velázquez; Tibor Vellai; Edo Vellenga; Francesca Velotti; Mireille Verdier; Panayotis Verginis; Isabelle Vergne; Paul Verkade; Manish Verma; Patrik Verstreken; Tim Vervliet; Jörg Vervoorts; Alexandre T Vessoni; Victor M Victor; Michel Vidal; Chiara Vidoni; Otilia V Vieira; Richard D Vierstra; Sonia Viganó; Helena Vihinen; Vinoy Vijayan; Miquel Vila; Marçal Vilar; José M Villalba; Antonio Villalobo; Beatriz Villarejo-Zori; Francesc Villarroya; Joan Villarroya; Olivier Vincent; Cecile Vindis; Christophe Viret; Maria Teresa Viscomi; Dora Visnjic; Ilio Vitale; David J Vocadlo; Olga V Voitsekhovskaja; Cinzia Volonté; Mattia Volta; Marta Vomero; Clarissa Von Haefen; Marc A Vooijs; Wolfgang Voos; Ljubica Vucicevic; Richard Wade-Martins; Satoshi Waguri; Kenrick A Waite; Shuji Wakatsuki; David W Walker; Mark J Walker; Simon A Walker; Jochen Walter; Francisco G Wandosell; Bo Wang; Chao-Yung Wang; Chen Wang; Chenran Wang; Chenwei Wang; Cun-Yu Wang; Dong Wang; Fangyang Wang; Feng Wang; Fengming Wang; Guansong Wang; Han Wang; Hao Wang; Hexiang Wang; Hong-Gang Wang; Jianrong Wang; Jigang Wang; Jiou Wang; Jundong Wang; Kui Wang; Lianrong Wang; Liming Wang; Maggie Haitian Wang; Meiqing Wang; Nanbu Wang; Pengwei Wang; Peipei Wang; Ping Wang; Ping Wang; Qing Jun Wang; Qing Wang; Qing Kenneth Wang; Qiong A Wang; Wen-Tao Wang; Wuyang Wang; Xinnan Wang; Xuejun Wang; Yan Wang; Yanchang Wang; Yanzhuang Wang; Yen-Yun Wang; Yihua Wang; Yipeng Wang; Yu Wang; Yuqi Wang; Zhe Wang; Zhenyu Wang; Zhouguang Wang; Gary Warnes; Verena Warnsmann; Hirotaka Watada; Eizo Watanabe; Maxinne Watchon; Anna Wawrzyńska; Timothy E Weaver; Grzegorz Wegrzyn; Ann M Wehman; Huafeng Wei; Lei Wei; Taotao Wei; Yongjie Wei; Oliver H Weiergräber; Conrad C Weihl; Günther Weindl; Ralf Weiskirchen; Alan Wells; Runxia H Wen; Xin Wen; Antonia Werner; Beatrice Weykopf; Sally P Wheatley; J Lindsay Whitton; Alexander J Whitworth; Katarzyna Wiktorska; Manon E Wildenberg; Tom Wileman; Simon Wilkinson; Dieter Willbold; Brett Williams; Robin S B Williams; Roger L Williams; Peter R Williamson; Richard A Wilson; Beate Winner; Nathaniel J Winsor; Steven S Witkin; Harald Wodrich; Ute Woehlbier; Thomas Wollert; Esther Wong; Jack Ho Wong; Richard W Wong; Vincent Kam Wai Wong; W Wei-Lynn Wong; An-Guo Wu; Chengbiao Wu; Jian Wu; Junfang Wu; Kenneth K Wu; Min Wu; Shan-Ying Wu; Shengzhou Wu; Shu-Yan Wu; Shufang Wu; William K K Wu; Xiaohong Wu; Xiaoqing Wu; Yao-Wen Wu; Yihua Wu; Ramnik J Xavier; Hongguang Xia; Lixin Xia; Zhengyuan Xia; Ge Xiang; Jin Xiang; Mingliang Xiang; Wei Xiang; Bin Xiao; Guozhi Xiao; Hengyi Xiao; Hong-Tao Xiao; Jian Xiao; Lan Xiao; Shi Xiao; Yin Xiao; Baoming Xie; Chuan-Ming Xie; Min Xie; Yuxiang Xie; Zhiping Xie; Zhonglin Xie; Maria Xilouri; Congfeng Xu; En Xu; Haoxing Xu; Jing Xu; JinRong Xu; Liang Xu; Wen Wen Xu; Xiulong Xu; Yu Xue; Sokhna M S Yakhine-Diop; Masamitsu Yamaguchi; Osamu Yamaguchi; Ai Yamamoto; Shunhei Yamashina; Shengmin Yan; Shian-Jang Yan; Zhen Yan; Yasuo Yanagi; Chuanbin Yang; Dun-Sheng Yang; Huan Yang; Huang-Tian Yang; Hui Yang; Jin-Ming Yang; Jing Yang; Jingyu Yang; Ling Yang; Liu Yang; Ming Yang; Pei-Ming Yang; Qian Yang; Seungwon Yang; Shu Yang; Shun-Fa Yang; Wannian Yang; Wei Yuan Yang; Xiaoyong Yang; Xuesong Yang; Yi Yang; Ying Yang; Honghong Yao; Shenggen Yao; Xiaoqiang Yao; Yong-Gang Yao; Yong-Ming Yao; Takahiro Yasui; Meysam Yazdankhah; Paul M Yen; Cong Yi; Xiao-Ming Yin; Yanhai Yin; Zhangyuan Yin; Ziyi Yin; Meidan Ying; Zheng Ying; Calvin K Yip; Stephanie Pei Tung Yiu; Young H Yoo; Kiyotsugu Yoshida; Saori R Yoshii; Tamotsu Yoshimori; Bahman Yousefi; Boxuan Yu; Haiyang Yu; Jun Yu; Jun Yu; Li Yu; Ming-Lung Yu; Seong-Woon Yu; Victor C Yu; W Haung Yu; Zhengping Yu; Zhou Yu; Junying Yuan; Ling-Qing Yuan; Shilin Yuan; Shyng-Shiou F Yuan; Yanggang Yuan; Zengqiang Yuan; Jianbo Yue; Zhenyu Yue; Jeanho Yun; Raymond L Yung; David N Zacks; Gabriele Zaffagnini; Vanessa O Zambelli; Isabella Zanella; Qun S Zang; Sara Zanivan; Silvia Zappavigna; Pilar Zaragoza; Konstantinos S Zarbalis; Amir Zarebkohan; Amira Zarrouk; Scott O Zeitlin; Jialiu Zeng; Ju-Deng Zeng; Eva Žerovnik; Lixuan Zhan; Bin Zhang; Donna D Zhang; Hanlin Zhang; Hong Zhang; Hong Zhang; Honghe Zhang; Huafeng Zhang; Huaye Zhang; Hui Zhang; Hui-Ling Zhang; Jianbin Zhang; Jianhua Zhang; Jing-Pu Zhang; Kalin Y B Zhang; Leshuai W Zhang; Lin Zhang; Lisheng Zhang; Lu Zhang; Luoying Zhang; Menghuan Zhang; Peng Zhang; Sheng Zhang; Wei Zhang; Xiangnan Zhang; Xiao-Wei Zhang; Xiaolei Zhang; Xiaoyan Zhang; Xin Zhang; Xinxin Zhang; Xu Dong Zhang; Yang Zhang; Yanjin Zhang; Yi Zhang; Ying-Dong Zhang; Yingmei Zhang; Yuan-Yuan Zhang; Yuchen Zhang; Zhe Zhang; Zhengguang Zhang; Zhibing Zhang; Zhihai Zhang; Zhiyong Zhang; Zili Zhang; Haobin Zhao; Lei Zhao; Shuang Zhao; Tongbiao Zhao; Xiao-Fan Zhao; Ying Zhao; Yongchao Zhao; Yongliang Zhao; Yuting Zhao; Guoping Zheng; Kai Zheng; Ling Zheng; Shizhong Zheng; Xi-Long Zheng; Yi Zheng; Zu-Guo Zheng; Boris Zhivotovsky; Qing Zhong; Ao Zhou; Ben Zhou; Cefan Zhou; Gang Zhou; Hao Zhou; Hong Zhou; Hongbo Zhou; Jie Zhou; Jing Zhou; Jing Zhou; Jiyong Zhou; Kailiang Zhou; Rongjia Zhou; Xu-Jie Zhou; Yanshuang Zhou; Yinghong Zhou; Yubin Zhou; Zheng-Yu Zhou; Zhou Zhou; Binglin Zhu; Changlian Zhu; Guo-Qing Zhu; Haining Zhu; Hongxin Zhu; Hua Zhu; Wei-Guo Zhu; Yanping Zhu; Yushan Zhu; Haixia Zhuang; Xiaohong Zhuang; Katarzyna Zientara-Rytter; Christine M Zimmermann; Elena Ziviani; Teresa Zoladek; Wei-Xing Zong; Dmitry B Zorov; Antonio Zorzano; Weiping Zou; Zhen Zou; Zhengzhi Zou; Steven Zuryn; Werner Zwerschke; Beate Brand-Saberi; X Charlie Dong; Chandra Shekar Kenchappa; Zuguo Li; Yong Lin; Shigeru Oshima; Yueguang Rong; Judith C Sluimer; Christina L Stallings; Chun-Kit Tong
Journal:  Autophagy       Date:  2021-02-08       Impact factor: 13.391

Review 3.  Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies.

Authors:  Fiona Limanaqi; Francesca Biagioni; Stefano Gambardella; Pietro Familiari; Alessandro Frati; Francesco Fornai
Journal:  Int J Mol Sci       Date:  2020-04-24       Impact factor: 5.923

4.  RCAN1 Inhibits BACE2 Turnover by Attenuating Proteasome-Mediated BACE2 Degradation.

Authors:  Kaixin Qiu; Shuai Wang; Xin Wang; Fengting Wang; Yili Wu
Journal:  Biomed Res Int       Date:  2020-06-05       Impact factor: 3.411

5.  STAT1 maintains naïve CD8+ T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.

Authors:  Yoon-Chul Kye; Gil-Woo Lee; Sung-Woo Lee; Young-Jun Ju; Hee-Ok Kim; Cheol-Heui Yun; Jae-Ho Cho
Journal:  Sci Adv       Date:  2021-09-01       Impact factor: 14.136

Review 6.  The Role of HDAC6 in Autophagy and NLRP3 Inflammasome.

Authors:  Panpan Chang; Hao Li; Hui Hu; Yongqing Li; Tianbing Wang
Journal:  Front Immunol       Date:  2021-10-27       Impact factor: 7.561

Review 7.  Relationship between lysosomal dyshomeostasis and progression of diabetic kidney disease.

Authors:  Man Wu; Minjie Zhang; Yaozhi Zhang; Zixian Li; Xingyu Li; Zejian Liu; Huafeng Liu; Xiaoyu Li
Journal:  Cell Death Dis       Date:  2021-10-18       Impact factor: 8.469

8.  Mystery of methamphetamine-induced autophagosome accumulation in hippocampal neurons: loss of syntaxin 17 in defects of dynein-dynactin driving and autophagosome-late endosome/lysosome fusion.

Authors:  Huaisha Xu; Yuanhui Zhu; Xufeng Chen; Tingyu Yang; Xi Wang; Xu Song; Xuexue Xie; Miaoyang Hu; Lei Jiang; Jie Cheng; Rong Gao; Jun Wang
Journal:  Arch Toxicol       Date:  2021-08-10       Impact factor: 5.153

9.  Flavan-3-ol Microbial Metabolites Modulate Proteolysis in Neuronal Cells Reducing Amyloid-beta (1-42) Levels.

Authors:  Valentina Cecarini; Massimiliano Cuccioloni; Yadong Zheng; Laura Bonfili; Chunmei Gong; Mauro Angeletti; Pedro Mena; Daniele Del Rio; Anna Maria Eleuteri
Journal:  Mol Nutr Food Res       Date:  2021-08-07       Impact factor: 6.575

10.  Tissue-Specific Impact of Autophagy Genes on the Ubiquitin-Proteasome System in C. elegans.

Authors:  Sweta Jha; Carina I Holmberg
Journal:  Cells       Date:  2020-08-08       Impact factor: 6.600
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