AI Article Synopsis

  • Macroautophagy involves creating structures called autophagosomes for cellular cleanup, and disrupting their closure has unknown effects.
  • Researchers created mice with a specific mutation that impairs autophagosome closure, resulting in various issues like protein buildup and growth problems, though some survive into adulthood.
  • The study found that this mutation causes the buildup of a protein (TBK1) on forming autophagosomes, leading to increased phosphorylation and aggregation of other proteins, suggesting a new role for these structures in managing cellular waste.

Article Abstract

Macroautophagy (autophagy) involves the formation of phagophores that mature into autophagosomes. The impact of inhibiting autophagosome closure remains unclear. Here, we report the generation and analysis of mice with impaired autophagosome closure by targeting the ubiquitin E2 variant-like (UEVL) β strands of the endosomal sorting complex required for transport (ESCRT) I subunit VPS37A. The VPS37A UEVL mutation (Δ43-139) impairs bulk autophagic flux without disrupting ESCRT-I complex assembly and endosomal function. Homozygous mutant mice exhibit signs of autophagy impairment, including p62/SQSTM1 and ubiquitinated protein accumulation, neuronal dysfunction, growth retardation, antioxidant gene upregulation, and tissue abnormalities. However, about half of the mutant neonates survive to adulthood without severe liver injury. LC3 proximity proteomics reveals that the VPS37A UEVL mutation leads to active TANK-binding kinase 1 (TBK1) accumulation on phagophores, resulting in increased p62 phosphorylation and inclusion formation. These findings reveal a previously unappreciated role of LC3-conjugated phagophores in facilitating protein aggregation and sequestration, potentially alleviating proteotoxicity.

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Source
http://dx.doi.org/10.1016/j.celrep.2024.115016DOI Listing

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