title: TOR complex 2-Ypk1 signaling is an essential positive regulator of the general amino acid control response and autophagy.
abstract: The highly conserved Target of Rapamycin (TOR) kinase is a central regulator of cell growth and metabolism in response to nutrient availability. TOR functions in two structurally and functionally distinct complexes, TOR Complex 1 (TORC1) and TOR Complex 2 (TORC2). Through TORC1, TOR negatively regulates autophagy, a conserved process that functions in quality control and cellular homeostasis and, in this capacity, is part of an adaptive nutrient deprivation response. Here we demonstrate that during amino acid starvation TOR also operates independently as a positive regulator of autophagy through the conserved TORC2 and its downstream target protein kinase, Ypk1. Under these conditions, TORC2-Ypk1 signaling negatively regulates the Ca(2+)/calmodulin-dependent phosphatase, calcineurin, to enable the activation of the amino acid-sensing eIF2α kinase, Gcn2, and to promote autophagy. Our work reveals that the TORC2 pathway regulates autophagy in an opposing manner to TORC1 to provide a tunable response to cellular metabolic status.
authors.affiliation: Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA 95616.
authors.forename: Ariadne
authors.initials: A
authors.lastname: Vlahakis
authors.affiliation: Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA 95616.
authors.forename: Martin
authors.initials: M
authors.lastname: Graef
authors.affiliation: Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA 95616.
authors.forename: Jodi
authors.initials: J
authors.lastname: Nunnari
authors.affiliation: Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA 95616 tpowers@ucdavis.edu.
authors.forename: Ted
authors.initials: T
authors.lastname: Powers
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D019703:Calcineurin / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D046912:Multiprotein Complexes; D029701:Saccharomyces cerevisiae Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; C068124:MCK1 protein, S cerevisiae; D019703:Calcineurin
keywords: Atg8; Gcn4