title: ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery.
abstract: Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Chang Hwa
authors.initials: CH
authors.lastname: Jung
authors.forename: Chang Bong
authors.initials: CB
authors.lastname: Jun
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ro
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Neil Michael
authors.initials: NM
authors.lastname: Otto
authors.forename: Jing
authors.initials: J
authors.lastname: Cao
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
authors.forename: Do-Hyung
authors.initials: DH
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D010588:Phagosomes / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: C534291:ATG13 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D047908:Intracellular Signaling Peptides and Proteins; C407704:RB1CC1 protein, human; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D011505:Protein-Tyrosine Kinases; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse; C541703:Ulk2 protein, human