ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase

Ryan C. Russell, Ye Tian, Haixin Yuan, Hyun Woo Park, Yu Yun Chang, Joungmok Kim, Haerin Kim, Thomas P. Neufeld, Andrew Dillin, Kun Liang Guan

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1027 Citations (Scopus)


Autophagy is the primary cellular catabolic program activated in response to nutrient starvation. Initiation of autophagy, particularly by amino-acid withdrawal, requires the ULK kinases. Despite its pivotal role in autophagy initiation, little is known about the mechanisms by which ULK promotes autophagy. Here we describe a molecular mechanism linking ULK to the pro-autophagic lipid kinase VPS34. Following amino-acid starvation or mTOR inhibition, the activated ULK1 phosphorylates Beclin-1 on Ser 14, thereby enhancing the activity of the ATG14L-containing VPS34 complexes. The Beclin-1 Ser 14 phosphorylation by ULK is required for full autophagic induction in mammals and this requirement is conserved in Caenorhabditis elegans. Our study reveals a molecular link from ULK1 to activation of the autophagy-specific VPS34 complex and autophagy induction.

Original languageEnglish
Pages (from-to)741-750
Number of pages10
JournalNature Cell Biology
Issue number7
Publication statusPublished - 2013 Jul

Bibliographical note

Funding Information:
We would like to thank H. Zhang for LGG-1 and PGL-1 antibodies; J. Jewell, C. Hansen and K. Tumaneng for critical reading of this manuscript; and M. Farquhar for electron microscopy. Phosphosite identification by mass spectrometry was performed by the Proteomics Facility at the Fred Hutchinson Cancer Research Center. Confocal analysis was performed at the UCSD Neuroscience Microscopy Shared Facility (Grant P30 NS047101). This work was supported by National Institutes of Health (NIH) grants GM51586, GM62694 and CA108941, and the Department of Defense (W81XWH-0901-0279). R.C.R. is supported by a Canadian Institutes of Health Research (CIHR) postdoctoral fellowship.

All Science Journal Classification (ASJC) codes

  • Cell Biology


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