title: Transcriptional regulation by Pho23 modulates the frequency of autophagosome formation.
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.
authors.affiliation: Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Jin
authors.affiliation: Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: He
authors.affiliation: Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Backues
authors.affiliation: Life Sciences Institute and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Mallory A
authors.initials: MA
authors.lastname: Freeberg
authors.affiliation: Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Life Sciences Institute and Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: klionsky@umich.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klionsky
mesh_terms: D001343:Autophagy; D000071183:Autophagy-Related Proteins; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010588:Phagosomes / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C434065:ATG9 protein, S cerevisiae; D000071183:Autophagy-Related Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C432409:Pho23 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins