AI Article Synopsis
- The study investigates the role of the ESCRT-III subunit CHMP2A and the AAA ATPase VPS4 in the closure of phagophores, which are essential for forming autophagosomes.
- Researchers developed a FACS-based assay to identify VPS37A, an ESCRT-I subunit, as a key player in completing phagophore closure, highlighting its unique localization and function.
- VPS37A is necessary for the recruitment of other ESCRT components during phagophore closure while showing that disruptions in related proteins can affect its presence on the phagophore, suggesting it manages the assembly of specific ESCRT machinery in this process.
Article Abstract
The process of phagophore closure requires the endosomal sorting complex required for transport III (ESCRT-III) subunit CHMP2A and the AAA ATPase VPS4, but their regulatory mechanisms remain unknown. Here, we establish a FACS-based HaloTag-LC3 autophagosome completion assay to screen a genome-wide CRISPR library and identify the ESCRT-I subunit VPS37A as a critical component for phagophore closure. VPS37A localizes on the phagophore through the N-terminal putative ubiquitin E2 variant domain, which is found to be required for autophagosome completion but dispensable for ESCRT-I complex formation and the degradation of epidermal growth factor receptor in the multivesicular body pathway. Notably, loss of VPS37A abrogates the phagophore recruitment of the ESCRT-I subunit VPS28 and CHMP2A, whereas inhibition of membrane closure by CHMP2A depletion or VPS4 inhibition accumulates VPS37A on the phagophore. These observations suggest that VPS37A coordinates the recruitment of a unique set of ESCRT machinery components for phagophore closure in mammalian cells.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781443 | PMC |
| http://dx.doi.org/10.1083/jcb.201902170 | DOI Listing |
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