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Mammalian hybrid pre-autophagosomal structure HyPAS generates autophagosomes

ABSTRACT: The biogenesis of mammalian autophagosomes remains to be fully defined. Here we used cellular and in vitro membrane fusion analyses to show that autophagosomes are formed from a hitherto unappreciated hybrid membrane compartment. The autophagic precursors emerge through fusion of FIP200 vesicles, derived from the cis-Golgi, with endosomally-derived ATG16L1 membranes to generate a hybrid pre-autophagosomal structure, HyPAS. HyPAS biogenesis depends on a previously unrecognized machinery centered upon STX17 interactors, the calcium pump SERCA2, extended synaptotagmin E-SYT2, and SIGMAR1. This apparatus controls HyPAS biogenesis and defines the mammalian autophagosomal precursor membranes. HyPAS can be modulated by pharmacological agents whereas its formation is inhibited upon SARS-CoV-2 infection or by expression of SARS-CoV-2 nsp6. These findings reveal the origin of mammalian autophagosomal membranes that emerge via convergence of secretory and endosomal pathways, and that this process is targeted by microbial factors such as coronaviral membrane modulating proteins.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Vojo Deretic

PROVIDER: MSV000087840 | MassIVE | Fri Jul 16 15:40:00 BST 2021

SECONDARY ACCESSION(S): PXD027373

REPOSITORIES: MassIVE

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