Meiyan Jin1, Ding He1, Steven K Backues1, Mallory A Freeberg2, Xu Liu1, John K Kim3, Daniel J Klionsky4. 1. Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. 2. Life Sciences Institute and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. 3. Life Sciences Institute and Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. 4. Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: klionsky@umich.edu.
Abstract
BACKGROUND: Autophagy as a conserved lysosomal/vacuolar degradation and recycling pathway is important in normal development and physiology, and defects in this process are linked to many kinds of disease. Because too much or too little autophagy can be detrimental, the process must be tightly regulated both temporally and in magnitude. Two parameters that affect this regulation are the size and the number of autophagosomes; however, although we know that the amount of Atg8 affects the size of autophagosomes, the mechanism for regulating their number has not been elucidated. The transcriptional induction and repression of the autophagy-related (ATG) genes is one crucial aspect of autophagy regulation, but the transcriptional regulators that modulate autophagy are not well characterized. RESULTS: We detected increased expression levels of ATG genes, and elevated autophagy activity, in cells lacking the transcriptional regulator Pho23. Using transmission electron microscopy, we found that PHO23 null mutant cells contain significantly more autophagosomes than the wild-type. By RNA sequencing transcriptome profiling, we identified ATG9 as one of the key targets of Pho23, and our studies with strains expressing modulated levels of Atg9 show that the amount of this protein directly correlates with the frequency of autophagosome formation and the level of autophagy activity. CONCLUSIONS: Our results identified Pho23 as a master transcriptional repressor for autophagy that regulates the frequency of autophagosome formation through its negative regulation of ATG9.
BACKGROUND: Autophagy as a conserved lysosomal/vacuolar degradation and recycling pathway is important in normal development and physiology, and defects in this process are linked to many kinds of disease. Because too much or too little autophagy can be detrimental, the process must be tightly regulated both temporally and in magnitude. Two parameters that affect this regulation are the size and the number of autophagosomes; however, although we know that the amount of Atg8 affects the size of autophagosomes, the mechanism for regulating their number has not been elucidated. The transcriptional induction and repression of the autophagy-related (ATG) genes is one crucial aspect of autophagy regulation, but the transcriptional regulators that modulate autophagy are not well characterized. RESULTS: We detected increased expression levels of ATG genes, and elevated autophagy activity, in cells lacking the transcriptional regulator Pho23. Using transmission electron microscopy, we found that PHO23 null mutant cells contain significantly more autophagosomes than the wild-type. By RNA sequencing transcriptome profiling, we identified ATG9 as one of the key targets of Pho23, and our studies with strains expressing modulated levels of Atg9 show that the amount of this protein directly correlates with the frequency of autophagosome formation and the level of autophagy activity. CONCLUSIONS: Our results identified Pho23 as a master transcriptional repressor for autophagy that regulates the frequency of autophagosome formation through its negative regulation of ATG9.
Authors: S V Scott; D C Nice; J J Nau; L S Weisman; Y Kamada; I Keizer-Gunnink; T Funakoshi; M Veenhuis; Y Ohsumi; D J Klionsky Journal: J Biol Chem Date: 2000-08-18 Impact factor: 5.157
Authors: Daniel J Klionsky; James M Cregg; William A Dunn; Scott D Emr; Yasuyoshi Sakai; Ignacio V Sandoval; Andrei Sibirny; Suresh Subramani; Michael Thumm; Marten Veenhuis; Yoshinori Ohsumi Journal: Dev Cell Date: 2003-10 Impact factor: 12.270
Authors: A P Gasch; P T Spellman; C M Kao; O Carmel-Harel; M B Eisen; G Storz; D Botstein; P O Brown Journal: Mol Biol Cell Date: 2000-12 Impact factor: 4.138
Authors: Vinay V Eapen; David P Waterman; Amélie Bernard; Nathan Schiffmann; Enrich Sayas; Roarke Kamber; Brenda Lemos; Gonen Memisoglu; Jessie Ang; Allison Mazella; Silvia G Chuartzman; Robbie J Loewith; Maya Schuldiner; Vladimir Denic; Daniel J Klionsky; James E Haber Journal: Proc Natl Acad Sci U S A Date: 2017-02-02 Impact factor: 11.205