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Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress

Title
Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress
Authors
Peng H.Yang J.Li G.You Q.Han W.Li T.Gao D.Xie X.Lee, Byung HoonDu J.Hou J.Zhang T.Rao H.Huang Y.Li Q.Zeng R.Hui L.Wang H.Xia Q.Zhang X.He Y.Komatsu M.Dikic I.Finley D.Hu R.
DGIST Authors
Lee, Byung Hoon
Issue Date
2017-05
Citation
Cell Research, 27(5), 657-674
Type
Article
Article Type
Article
Keywords
autophagy receptorubiquitylationheat shockdynamic light scatteringubiquitinselective autophagy
ISSN
1001-0602
Abstract
Alterations in cellular ubiquitin (Ub) homeostasis, known as Ub stress, feature and affect cellular responses in multiple conditions, yet the underlying mechanisms are incompletely understood. Here we report that autophagy receptor p62/sequestosome-1 interacts with E2 Ub conjugating enzymes, UBE2D2 and UBE2D3. Endogenous p62 undergoes E2-dependent ubiquitylation during upregulation of Ub homeostasis, a condition termed as Ub + stress, that is intrinsic to Ub overexpression, heat shock or prolonged proteasomal inhibition by bortezomib, a chemotherapeutic drug. Ubiquitylation of p62 disrupts dimerization of the UBA domain of p62, liberating its ability to recognize polyubiquitylated cargoes for selective autophagy. We further demonstrate that this mechanism might be critical for autophagy activation upon Ub + stress conditions. Delineation of the mechanism and regulatory roles of p62 in sensing Ub stress and controlling selective autophagy could help to understand and modulate cellular responses to a variety of endogenous and environmental challenges, potentially opening a new avenue for the development of therapeutic strategies against autophagy-related maladies. © 2017 IBCB, SIBS, CAS All rights reserved.
URI
http://hdl.handle.net/20.500.11750/6531
DOI
10.1038/cr.2017.40
Publisher
Nature Publishing Group
Related Researcher
  • Author Lee, Byung-Hoon Lab of Protein Homeostasis and Drug Discovery
  • Research Interests Ubiquitin-proteasome system; Protein homeostasis; Small-molecule chemical screening and drug discovery in human disease
Files:
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Collection:
Department of New BiologyLab of Protein Homeostasis and Drug Discovery1. Journal Articles


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