title: E1-like activating enzyme Atg7 is preferentially sequestered into p62 aggregates via its interaction with LC3-I.
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.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Wentao
authors.initials: W
authors.lastname: Gao
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Michael T
authors.initials: MT
authors.lastname: Stang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000378:metabolism; D011485:Protein Binding; D000071456:Sequestosome-1 Protein; D013379:Substrate Specificity; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; D010714:Phosphatidylethanolamines; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C483858:phosphatidylethanolamine; D044763:Ubiquitin-Conjugating Enzymes; C507524:ATG4B protein, human; D003546:Cysteine Endopeptidases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; C455621:ATG3 protein, human
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