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Nat Commun. 2018 Nov 13;9(1):4770. doi: 10.1038/s41467-018-07185-y.

Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN.

Liu B1,2,3, Jiang S3,4, Li M1, Xiong X1, Zhu M3,4, Li D2, Zhao L3, Qian L3,4, Zhai L3, Li J5, Lu H6, Sun S3, Lin J7, Lu Y8, Li X9, Tan M10,11.

Author information

1
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan Institute of Metabolic Diseases, Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Fudan University, Shanghai, 200032, PR China.
2
Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Huangshi, Hubei, 435003, PR China.
3
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
4
University of Chinese Academy of Sciences, Beijing, PR China.
5
Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
6
Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine (SJTU-SM), Shanghai, 200025, PR China.
7
Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, USA.
8
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan Institute of Metabolic Diseases, Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Fudan University, Shanghai, 200032, PR China. lu.yan2@zs-hospital.sh.cn.
9
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan Institute of Metabolic Diseases, Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Fudan University, Shanghai, 200032, PR China. li.xiaoying@zs-hospital.sh.cn.
10
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. mjtan@simm.ac.cn.
11
University of Chinese Academy of Sciences, Beijing, PR China. mjtan@simm.ac.cn.

Abstract

Ubiquitin-specific protease 14 (USP14) is one of the major proteasome-associated deubiquitinating enzymes critical for proteome homeostasis. However, substrates of USP14 remain largely unknown, hindering the understanding of its functional roles. Here we conduct a comprehensive proteome, ubiquitinome and interactome analysis for USP14 substrate screening. Bioinformatics analysis reveals broad new potential roles of USP14, especially in lipid and carbohydrate metabolism. Among the potential substrates identified, we show that fatty acid synthase (FASN), a key enzyme involved in hepatic lipogenesis, is a bona fide substrate of USP14. USP14 directly interacts with and increases FASN stability. As a result, overexpression of USP14 promotes liver triglyceride accumulation in C57BL/6 mice, whereas genetic ablation or pharmacological inhibition of USP14 ameliorates hepatosteatosis, hyperglycemia and insulin resistance in obese mice. In conclusion, our findings reveal for the first time an indispensable role of USP14 in hepatosteatosis through FASN stabilization.

PMID:
30425250
PMCID:
PMC6233205
DOI:
10.1038/s41467-018-07185-y
[Indexed for MEDLINE]
Free PMC Article

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