Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress.
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.
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.|Graduate School, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.|Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Hong
H
Peng
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.|Graduate School, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.|Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Jiao
J
Yang
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.|Graduate School, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Guangyi
G
Li
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.|Graduate School, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Qing
Q
You
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.
Wen
W
Han
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.
Tianrang
T
Li
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.
Daming
D
Gao
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.
Xiaoduo
X
Xie
Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.
Byung-Hoon
BH
Lee
Department of Hematology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
Juan
J
Du
Department of Hematology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
Jian
J
Hou
Department of Laboratory Medicine, Huashan Hospital, Fudan University, 12 Central Urumqi Road, Shanghai 200040, China.
Tao
T
Zhang
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Hai
H
Rao
Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Ying
Y
Huang
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.
Qinrun
Q
Li
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.
Rong
R
Zeng
Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Lijian
L
Hui
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.
Hongyan
H
Wang
State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
Qin
Q
Xia
State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
Xuemin
X
Zhang
Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Yongning
Y
He
Department of Biochemistry, School of Medicine Niigata University, 757, Ichibancho, Asahimachidori, Chuo-ku, Niigata 951-8510, Japan.
Masaaki
M
Komatsu
Molecular Signaling, Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt am Main, Germany.
Ivan
I
Dikic
Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.
Daniel
D
Finley
Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai 200031, China.
Ronggui
R
Hu
D000818:Animals; D001343:Autophagy; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D018869:Heat-Shock Response; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D000071456:Sequestosome-1 Protein / Q000737:chemistry / Q000378:metabolism*; D013312:Stress, Physiological; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D054875:Ubiquitination
D061988:Proteasome Inhibitors; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin; D025821:Polyubiquitin; D010768:Phosphoserine; C097309:UBE2D2 protein, human; C097310:UBE2D3 protein, human; D044763:Ubiquitin-Conjugating Enzymes