CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to Regulate Cell Proliferation and Autophagy

Liyan Gong; Kaihua Wang; Mengcheng Wang; Ronggui Hu; Huaguang Li; Daming Gao; Moubin Lin

doi:10.3389/fcell.2021.684885

CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to Regulate Cell Proliferation and Autophagy

Front Cell Dev Biol. 2021 Jun 7:9:684885. doi: 10.3389/fcell.2021.684885. eCollection 2021.

Authors

Liyan Gong^{1

2}, Kaihua Wang^{3

4}, Mengcheng Wang^{3

4}, Ronggui Hu^{4

5}, Huaguang Li¹, Daming Gao^{3

4}, Moubin Lin^{1

2}

Affiliations

¹ Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
² Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
³ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
⁴ University of Chinese Academy of Sciences, Beijing, China.
⁵ State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.

Abstract

p62/SQSTM1 (sequestosome-1) is a key protein involved in multiple cellular bioprocesses including autophagy, nutrient sensing, cell growth, cell death, and survival. Therefore, it is implicated in human diseases such as obesity and cancer. Here, we show that the CUL5-ASB6 complex is a ubiquitin E3 ligase complex mediating p62 ubiquitination and degradation. Depletion of CUL5 or ASB6 induced p62 accumulation, and overexpression of ASB6 promoted ubiquitination and degradation of p62. Functionally, ASB6 overexpression can inhibit the proliferation of MEF and hepatocellular carcinoma cells by reducing p62 protein level, and impair the occurrence of autophagy. Overall, our study identified a new molecular mechanism regulating p62 stability, which may provide additional insights for understanding the delicate control of p62 and cell proliferation-autophagy control in physiological and pathological settings.

Keywords: ASB6; CUL5; autophagy; p62; proliferation; ubiquitination.