Journal
EMBO JOURNAL
Volume 40, Issue 14, Pages -Publisher
WILEY
DOI: 10.15252/embj.2020105985
Keywords
p62; PRKAG2; ULK1; VPS15
Categories
Funding
- Francis Crick Institute
- Cancer Research UK [C14801, A21211, FC001187, FC001999]
- UK Medical Research Council [FC001187, FC001999, MC_U105184308]
- Wellcome Trust [FC001187, FC001999]
- MRC [MC_U105184308] Funding Source: UKRI
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Autophagy is regulated by ULK and VPS15 through phosphorylation, affecting the formation and activity of autophagosomes. The study reveals the crucial role of VPS15 in autophagy and its association with ULK.
Autophagy is a process through which intracellular cargoes are catabolised inside lysosomes. It involves the formation of autophagosomes initiated by the serine/threonine kinase ULK and class III PI3 kinase VPS34 complexes. Here, unbiased phosphoproteomics screens in mouse embryonic fibroblasts deleted for Ulk1/2 reveal that ULK loss significantly alters the phosphoproteome, with novel high confidence substrates identified including VPS34 complex member VPS15 and AMPK complex subunit PRKAG2. We identify six ULK-dependent phosphorylation sites on VPS15, mutation of which reduces autophagosome formation in cells and VPS34 activity in vitro. Mutation of serine 861, the major VPS15 phosphosite, decreases both autophagy initiation and autophagic flux. Analysis of VPS15 knockout cells reveals two novel ULK-dependent phenotypes downstream of VPS15 removal that can be partially recapitulated by chronic VPS34 inhibition, starvation-independent accumulation of ULK substrates and kinase activity-regulated recruitment of autophagy proteins to ubiquitin-positive structures.
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