Abstract
Autophagy is an evolutionarily conserved pathway, in which cytoplasmic components are sequestered within double-membrane vesicles called autophagosomes and then transported into lysosomes or vacuoles for degradation. Over 40 conserved autophagy-related (ATG) genes define the core machinery for the five processes of autophagy: initiation, nucleation, elongation, closure, and fusion. In this review, we focus on one of the least well-characterized events in autophagy, namely the closure of the isolation membrane/phagophore to form the sealed autophagosome. This process is tightly regulated by ESCRT machinery, ATG proteins, Rab GTPase and Rab-related proteins, SNAREs, sphingomyelin, and calcium. We summarize recent progress in the regulation of autophagosome closure and discuss the key questions remaining to be addressed.
Highlights
Autophagy is a highly conserved pathway, in which cytoplasmic components are sequestered within double-membrane vesicles called autophagosomes, and transported into lysosomes or vacuoles for degradation [1,2,3]
The ATG2A–LC3 interaction region (LIR) mutant leads to the accumulation of immature and open isolation membrane (IM), whereas ATG2A–WIPI4 interaction is dispensable for autophagosome formation and autophagy flux [26]
They found that these two calcium modulators induce a block in autophagic flux after WIPI1 recruitment, but before the autophagosome closure, which leads to the production of unclosed autophagic structures [34]
Summary
Autophagy is a highly conserved pathway, in which cytoplasmic components are sequestered within double-membrane vesicles called autophagosomes, and transported into lysosomes or vacuoles for degradation [1,2,3]. In the budding yeast Saccharomyces cerevisiae, the ESCRT-III subunit Snf (CHMP4 in mammals) and the Vps ATPase localize to the IM, and their depletion results in the accumulation of unsealed autophagosomes decorated with multiple Atg proteins [19,20]. Zhen et al reported that the ESCRT-III component CHMP4B is recruited to the unsealed autophagosome during macroautophagy and mitophagy [18] They found that CHMP2A mediates mitophagosome sealing, and the depletion of CHMP2A results in the accumulation of CHMP4B on mitophagosomes [18]. The interaction between Snf and Atg is not dependent on Vps, suggesting the mechanism is different between selective and non-selective autophagy All these studies indicate that ESCRT complexes play an essential role in autophagosome closure during both non-selective and selective autophagy
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