The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14

Ji Man Park, Chang Hwa Jung, Minchul Seo, Neil Michael Otto, Douglas Grunwald, Kwan Hyun Kim, Branden Moriarity, Young Mi Kim, Colby Starker, Richard Seonghun Nho, Daniel Voytas, Do Hyung Kim

Research output: Contribution to journalArticlepeer-review

126 Scopus citations

Abstract

ULK1 (unc-51 like autophagy activating kinase 1), the key mediator of MTORC1 signaling to autophagy, regulates early stages of autophagosome formation in response to starvation or MTORC1 inhibition. How ULK1 regulates the autophagy induction process remains elusive. Here, we identify that ATG13, a binding partner of ULK1, mediates interaction of ULK1 with the ATG14-containing PIK3C3/VPS34 complex, the key machinery for initiation of autophagosome formation. The interaction enables ULK1 to phosphorylate ATG14 in a manner dependent upon autophagy inducing conditions, such as nutrient starvation or MTORC1 inhibition. The ATG14 phosphorylation mimics nutrient deprivation through stimulating the kinase activity of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex and facilitates phagophore and autophagosome formation. By monitoring the ATG14 phosphorylation, we determined that the ULK1 activity requires BECN1/Beclin 1 but not the phosphatidylethanolamine (PE)-conjugation machinery and the PIK3C3 kinase activity. Monitoring the phosphorylation also allowed us to identify that ATG9A is required to suppress the ULK1 activity under nutrient-enriched conditions. Furthermore, we determined that ATG14 phosphorylation depends on ULK1 and dietary conditions in vivo. These results define a key molecular event for the starvation-induced activation of the ATG14-containing PtdIns3K complex by ULK1, and demonstrate hierarchical relations between the ULK1 activation and other autophagy proteins involved in phagophore formation.

Original languageEnglish (US)
Pages (from-to)547-564
Number of pages18
JournalAutophagy
Volume12
Issue number3
DOIs
StatePublished - Apr 5 2016

Bibliographical note

Funding Information:
This study was supported by the functional proteomics of aging NIH training grant T32AG029796 (to NMO and DG); E0143033654 (to CHJ); HL114662 (to RSN); UL1TR000114 (to CS and DV); P30-DK050456, 7?12-BS-093, GM097057 and AG039758 (to DHK).

Publisher Copyright:
© 2016 Taylor & Francis.

Keywords

  • ATG13
  • ATG14
  • BECN1
  • MTORC1
  • PIK3C3
  • ULK1

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