title: The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy.
abstract: Macroautophagy (or autophagy) is a conserved degradative pathway that has been implicated in a number of biological processes, including organismal aging, innate immunity, and the progression of human cancers. This pathway was initially identified as a cellular response to nutrient deprivation and is essential for cell survival during these periods of starvation. Autophagy is highly regulated and is under the control of a number of signaling pathways, including the Tor pathway, that coordinate cell growth with nutrient availability. These pathways appear to target a complex of proteins that contains the Atg1 protein kinase. The data here show that autophagy in Saccharomyces cerevisiae is also controlled by the cAMP-dependent protein kinase (PKA) pathway. Elevated levels of PKA activity inhibited autophagy and inactivation of the PKA pathway was sufficient to induce a robust autophagy response. We show that in addition to Atg1, PKA directly phosphorylates Atg13, a conserved regulator of Atg1 kinase activity. This phosphorylation regulates Atg13 localization to the preautophagosomal structure, the nucleation site from which autophagy pathway transport intermediates are formed. Atg13 is also phosphorylated in a Tor-dependent manner, but these modifications appear to occur at positions distinct from the PKA phosphorylation sites identified here. In all, our data indicate that the PKA and Tor pathways function independently to control autophagy in S. cerevisiae, and that the Atg1/Atg13 kinase complex is a key site of signal integration within this degradative pathway.
authors.affiliation: Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Stephan
authors.forename: Yuh-Ying
authors.initials: YY
authors.lastname: Yeh
authors.forename: Vidhya
authors.initials: V
authors.lastname: Ramachandran
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Deminoff
authors.forename: Paul K
authors.initials: PK
authors.lastname: Herman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D015153:Blotting, Western; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C413216:ATG13 protein, S cerevisiae; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D008164:Luminescent Proteins; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C477823:ATG1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C500749:target of rapamycin protein, S cerevisiae; D017868:Cyclic AMP-Dependent Protein Kinases