Abstract
p62 is constitutively degraded by autophagy via its interaction with LC3. However, the interaction of p62 with LC3 species in the context of the LC3 lipidation process is not specified. Further, the p62-mediated protein aggregation’s effect on autophagy is unclear. We systemically analyzed the interactions of p62 with all known Atg proteins involved in LC3 lipidation. We find that p62 does not interact with LC3 at the stages when it is being processed by Atg4B or when it is complexed or conjugated with Atg3. p62 does interact with LC3-I and LC3-I:Atg7 complex and is preferentially recruited by LC3-II species under autophagic stimulation. Given that Atg4B, Atg3 and LC3-Atg3 are indispensable for LC3-II conversion, our study reveals a protective mechanism for Atg4B, Atg3 and LC3-Atg3 conjugate from being inappropriately sequestered into p62 aggregates. Our findings imply that p62 could potentially impair autophagy by negatively affecting LC3 lipidation and contribute to the development of protein aggregate diseases.
Highlights
Macroautophagy is a highly conserved cellular degradation process for senescent proteins and damaged organelles [1,2]
Our study reveals distinct p62 interactions with LC3 species in the course of LC3 lipidation
Our data may reflect the ability of p62 to negatively influence the LC3 lipidation process or LC3 lipidation could affect p62 turnover by autophagy
Summary
Macroautophagy (hereinafter referred to as autophagy) is a highly conserved cellular degradation process for senescent proteins and damaged organelles [1,2]. It is a process of cellular membrane trafficking characterized by a double membrane bound autophagosome engulfing intracellular targets [3,4]. In the Atg conjugation system, Atg forms an intermediate with an E1-like activating enzyme Atg via its C-terminal glycine residue. The lipidation process is completed by the putative E3-like enzyme Atg16L1:Atg5–Atg complex as LC3-Atg is exchanged with PE to form LC3-II [9]
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