Volume 27, No 5, May 2017

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 27 Issue 5, May 2017: 657-674

ORIGINAL ARTICLES

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

Hong Peng^1,2,3,*, Jiao Yang^1,2,3,*, Guangyi Li^1,2, Qing You^1,2, Wen Han¹, Tianrang Li¹, Daming Gao¹, Xiaoduo Xie¹, Byung-Hoon Lee⁴, Juan Du⁵, Jian Hou⁵, Tao Zhang⁶, Hai Rao⁷, Ying Huang³, Qinrun Li¹, Rong Zeng¹, Lijian Hui³, Hongyan Wang¹, Qin Xia⁸, Xuemin Zhang⁸, Yongning He³, Masaaki Komatsu⁹, Ivan Dikic¹⁰, Daniel Finley⁴ and Ronggui Hu¹

¹Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China
²Graduate School, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
³Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
⁴Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA
⁵Department of Hematology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China
⁶Department of Laboratory Medicine, Huashan Hospital, Fudan University, 12 Central Urumqi Road, Shanghai 200040, China
⁷Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA
⁸State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China
⁹Department of Biochemistry, School of Medicine Niigata University, 757, Ichibancho, Asahimachidori, Chuo-ku, Niigata 951-8510, Japan
¹⁰Molecular Signaling, Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt am Main, Germany Correspondence: Ronggui Hu,(coryhu@sibcb.ac.cn)

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.

10.1038/cr.2017.40

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