Physiological insights into ESCRT-mediated phagophore closure: potential cytoprotective roles for ATG8ylated membranes

The endosomal sorting complex required for transport (ESCRT) machinery is a membrane abscission system that mediates various intracellular membrane remodeling processes, including macroautophagy/autophagy. In our recent study, we established the unique requirement of the ubiquitin E2 variant-like (UEVL) domain of the ESCRT-I subunit VPS37A for phagophore closure, the final step in autophagosome biogenesis, and determined the physiological impact of systemically inhibiting closure by targeting this region in mice. While the mutant mice exhibited phenotypes similar to those reported in mice deficient in generating ATG8 (mammalian Atg8 homologs)-conjugated (ATG8ylated) phagophores, certain phenotypes, such as neonatal lethality and liver injury, were found to be notably milder. Further investigation revealed that ATG8ylated phagophores promote TBK1-dependent SQSTM1 phosphorylation and droplet formation, leading to the formation of large insoluble aggregates upon closure inhibition. These findings suggest potential roles for ATG8ylated membranes in mitigating proteotoxicity by efficiently concentrating and sequestering soluble, reactive microaggregates and converting them into less reactive, insoluble large aggregates. The study highlights VPS37A UEVL mutant mice as a model for investigating the physiological and pathological roles of phagophores that extend beyond degradation.