Bo Pan1, Jie Li1,2, Nirmal Parajuli1, Zongwen Tian1,3, Penglong Wu1,4, Megan T Lewno1, Jianqiu Zou2, Wenjuan Wang2,4, Lynn Bedford5, R John Mayer6, Jing Fang7, Jinbao Liu4, Taixing Cui8, Huabo Su1,2, Xuejun Wang1. 1. From the Division of Basic Biomedical Sciences, University of South Dakota, Sanford School of Medicine, Vermillion (B.P., J. Li, N.P., Z.T., P.W., M.T.L., H.S., X.W.). 2. Vascular Biology Center and Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University (J. Li, J.Z., W.W., H.S.). 3. Department of Anatomy, Wuhan University College of Basic Medical Sciences, Hubei, China (Z.T.). 4. Guangzhou Institute of Oncology, Tumor Hospital, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangdong, China (P.W., W.W., J. Liu). 5. School of Life Sciences, University of Nottingham, United Kingdom (L.B.). 6. The University of Nottingham Medical School, Queen's Medical Centre, United Kingdom (R.J.M.). 7. Department of Drug Discovery and Biomedical Sciences (J.F.), University of South Carolina College of Pharmacy, Columbia. 8. Department of Anatomy and Cell Biology (T.C.), University of South Carolina College of Pharmacy, Columbia.
Abstract
RATIONALE: The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime show cardiotoxicity. Moreover, UPS and autophagic-lysosomal pathway defects are implicated in cardiac pathogenesis. Hence, a better understanding of the cross-talk between the 2 catabolic pathways will help advance cardiac pathophysiology and medicine. OBJECTIVE: Systemic proteasome inhibition (PSMI) was shown to increase p62/SQSTM1 expression and induce myocardial macroautophagy. Here we investigate how proteasome malfunction activates cardiac autophagic-lysosomal pathway. METHODS AND RESULTS: Myocardial macroautophagy, TFEB (transcription factor EB) expression and activity, and p62 expression were markedly increased in mice with either cardiomyocyte-restricted ablation of Psmc1 (an essential proteasome subunit gene) or pharmacological PSMI. In cultured cardiomyocytes, PSMI-induced increases in TFEB activation and p62 expression were blunted by pharmacological and genetic calcineurin inhibition and by siRNA-mediated Molcn1 silencing. PSMI induced remarkable increases in myocardial autophagic flux in wild type mice but not p62 null (p62-KO) mice. Bortezomib-induced left ventricular wall thickening and diastolic malfunction was exacerbated by p62 deficiency. In cultured cardiomyocytes from wild type mice but not p62-KO mice, PSMI induced increases in LC3-II flux and the lysosomal removal of ubiquitinated proteins. Myocardial TFEB activation by PSMI as reflected by TFEB nuclear localization and target gene expression was strikingly less in p62-KO mice compared with wild type mice. CONCLUSIONS: (1) The activation of cardiac macroautophagy by proteasomal malfunction is mediated by the Mocln1-calcineurin-TFEB-p62 pathway; (2) p62 unexpectedly exerts a feed-forward effect on TFEB activation by proteasome malfunction; and (3) targeting the Mcoln1 (mucolipin1)-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac autophagic-lysosomal pathway activation during proteasome malfunction.
RATIONALE: The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime show cardiotoxicity. Moreover, UPS and autophagic-lysosomal pathway defects are implicated in cardiac pathogenesis. Hence, a better understanding of the cross-talk between the 2 catabolic pathways will help advance cardiac pathophysiology and medicine. OBJECTIVE: Systemic proteasome inhibition (PSMI) was shown to increase p62/SQSTM1 expression and induce myocardial macroautophagy. Here we investigate how proteasome malfunction activates cardiac autophagic-lysosomal pathway. METHODS AND RESULTS: Myocardial macroautophagy, TFEB (transcription factor EB) expression and activity, and p62 expression were markedly increased in mice with either cardiomyocyte-restricted ablation of Psmc1 (an essential proteasome subunit gene) or pharmacological PSMI. In cultured cardiomyocytes, PSMI-induced increases in TFEB activation and p62 expression were blunted by pharmacological and genetic calcineurin inhibition and by siRNA-mediated Molcn1 silencing. PSMI induced remarkable increases in myocardial autophagic flux in wild type mice but not p62 null (p62-KO) mice. Bortezomib-induced left ventricular wall thickening and diastolic malfunction was exacerbated by p62 deficiency. In cultured cardiomyocytes from wild type mice but not p62-KO mice, PSMI induced increases in LC3-II flux and the lysosomal removal of ubiquitinated proteins. Myocardial TFEB activation by PSMI as reflected by TFEB nuclear localization and target gene expression was strikingly less in p62-KO mice compared with wild type mice. CONCLUSIONS: (1) The activation of cardiac macroautophagy by proteasomal malfunction is mediated by the Mocln1-calcineurin-TFEB-p62 pathway; (2) p62 unexpectedly exerts a feed-forward effect on TFEB activation by proteasome malfunction; and (3) targeting the Mcoln1 (mucolipin1)-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac autophagic-lysosomal pathway activation during proteasome malfunction.
Authors: Huabo Su; Jie Li; Suchithra Menon; Jinbao Liu; Asangi R Kumarapeli; Ning Wei; Xuejun Wang Journal: Circ Res Date: 2010-11-04 Impact factor: 17.367
Authors: Hui-Ming Chang; Rohit Moudgil; Tiziano Scarabelli; Tochukwu M Okwuosa; Edward T H Yeh Journal: J Am Coll Cardiol Date: 2017-11-14 Impact factor: 24.094
Authors: Asangi R K Kumarapeli; Kathleen M Horak; Joseph W Glasford; Jie Li; Quanhai Chen; Jinbao Liu; Hanqiao Zheng; Xuejun Wang Journal: FASEB J Date: 2005-09-27 Impact factor: 5.191
Authors: Diego L Medina; Simone Di Paola; Ivana Peluso; Andrea Armani; Diego De Stefani; Rossella Venditti; Sandro Montefusco; Anna Scotto-Rosato; Carolina Prezioso; Alison Forrester; Carmine Settembre; Wuyang Wang; Qiong Gao; Haoxing Xu; Marco Sandri; Rosario Rizzuto; Maria Antonietta De Matteis; Andrea Ballabio Journal: Nat Cell Biol Date: 2015-03 Impact factor: 28.824
Authors: Shyam S Nandi; Kenichi Katsurada; Neeru M Sharma; Daniel R Anderson; Sushil K Mahata; Kaushik P Patel Journal: Am J Physiol Heart Circ Physiol Date: 2020-10-16 Impact factor: 4.733