Multilayered regulation of autophagy by the Atg1 kinase orchestrates spatial and temporal control of autophagosome formation
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Date
2021-12-16
Publication Type
Journal Article
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Abstract
Autophagy is a conserved intracellular degradation pathway exerting various cytoprotective and homeostatic functions by using de novo double-membrane vesicle (autophagosome) formation to target a wide range of cytoplasmic material for vacuolar/lysosomal degradation. The Atg1 kinase is one of its key regulators, coordinating a complex signaling program to orchestrate autophagosome formation. Combining in vitro reconstitution and cell-based approaches, we demonstrate that Atg1 is activated by lipidated Atg8 (Atg8-PE), stimulating substrate phosphorylation along the growing autophagosomal membrane. Atg1-dependent phosphorylation of Atg13 triggers Atg1 complex dissociation, enabling rapid turnover of Atg1 complex subunits at the pre-autophagosomal structure (PAS). Moreover, Atg1 recruitment by Atg8-PE self-regulates Atg8-PE levels in the growing autophagosomal membrane by phosphorylating and thus inhibiting the Atg8-specific E2 and E3. Our work uncovers the molecular basis for positive and negative feedback imposed by Atg1 and how opposing phosphorylation and dephosphorylation events underlie the spatiotemporal regulation of autophagy.
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published
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Journal / series
Volume
81 (24)
Pages / Article No.
5066 - 50810000000000
Publisher
Cell Press
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Subject
autophagy; signaling; phosphorylation; protein kinases; protein phosphatases; ubiquitin-like proteins; Atg8 lipidation; metabolism
Organisational unit
03595 - Peter, Matthias / Peter, Matthias
03663 - Aebersold, Rudolf (emeritus) / Aebersold, Rudolf (emeritus)
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Funding
161435 - The host-pathogen protein interactome of Mycobacterium tuberculosis (SNF)
670821 - Proteomics 4D: The proteome in context (EC)
670821 - Proteomics 4D: The proteome in context (EC)