Ubiquitin-specific peptidase 7 (USP7)-mediated deubiquitination of the histone deacetylase SIRT7 regulates gluconeogenesis

J Biol Chem. 2017 Aug 11;292(32):13296-13311. doi: 10.1074/jbc.M117.780130.

Lu Jiang ¹, Jiannan Xiong ¹, Junsi Zhan ¹, Fengjie Yuan ¹, Ming Tang ¹, Chaohua Zhang ¹, Ziyang Cao ¹, Yongcan Chen ¹, Xiaopeng Lu ¹, Yinglu Li ¹, Hui Wang ¹, Lina Wang ¹, Jiadong Wang ², Wei-Guo Zhu ³ ⁴ ⁵, Haiying Wang ⁶

Affiliations

1 From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center.
2 Institute of Systems Biomedicine, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191 and.
3 From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, zhuweiguo@bjmu.edu.cn.
4 Peking-Tsinghua University Center for Life Science, and.
5 the Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
6 From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Post-translational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, wendy@bjmu.edu.cn.

PMID: 28655758 DOI: 10.1074/jbc.M117.780130

Abstract

Sirtuin 7 (SIRT7), a member of the NAD⁺-dependent class III histone deacetylases, is involved in the regulation of various cellular processes and in resisting various stresses, such as hypoxia, low glucose levels, and DNA damage. Interestingly, SIRT7 is linked to the control of glycolysis, suggesting a role in glucose metabolism. Given the important roles of SIRT7, it is critical to clarify how SIRT7 activity is potentially regulated. It has been reported that some transcriptional and post-transcriptional regulatory mechanisms are involved. However, little is known how SIRT7 is regulated by the post-translational modifications. Here, we identified ubiquitin-specific peptidase 7 (USP7), a Deubiquitinase, as a negative regulator of SIRT7. We showed that USP7 interacts with SIRT7 both in vitro and in vivo, and we further demonstrated that SIRT7 undergoes endogenous Lys-63-linked polyubiquitination, which is removed by USP7. Although the USP7-mediated deubiquitination of SIRT7 had no effect on its stability, the deubiquitination repressed its enzymatic activity. We also showed that USP7 coordinates with SIRT7 to regulate the expression of glucose-6-phosphatase catalytic subunit (G6PC), a gluconeogenic gene. USP7 depletion by RNA interference increased both G6PC expression and SIRT7 enzymatic activity. Moreover, SIRT7 targeted the G6PC promoter through the transcription factor ELK4 but not through forkhead box O1 (FoxO1). In summary, SIRT7 is a USP7 substrate and has a novel role as a regulator of gluconeogenesis. Our study may provide the basis for new clinical approaches to treat metabolic disorders related to glucose metabolism.

Keywords

deubiquitylation (deubiquitination); gene expression; gluconeogenesis; post-translational modification; sirtuin.

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