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

Hong Peng, Jiao Yang, Guangyi Li, Qing You, Wen Han, Tianrang Li, Daming Gao, Xiaoduo Xie, Byung Hoon Lee, Juan Du, Jian Hou, Tao Zhang, Hai Rao, Ying Huang, Qinrun Li, Rong Zeng, Lijian Hui, Hongyan Wang, Qin Xia, Xuemin ZhangYongning He, Masaaki Komatsu, Ivan Dikic, Daniel Finley, Ronggui Hu

Research output: Contribution to journalArticle

48 Scopus citations

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.Cell Research advance online publication 21 March 2017; doi:10.1038/cr.2017.40.

Original languageEnglish (US)
JournalCell Research
DOIs
StateAccepted/In press - Mar 21 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Peng, H., Yang, J., Li, G., You, Q., Han, W., Li, T., Gao, D., Xie, X., Lee, B. H., Du, J., Hou, J., Zhang, T., Rao, H., Huang, Y., Li, Q., Zeng, R., Hui, L., Wang, H., Xia, Q., ... Hu, R. (Accepted/In press). Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress. Cell Research. https://doi.org/10.1038/cr.2017.40