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

Bin Liu, Shangwen Jiang, Min Li, Xuelian Xiong, Mingrui Zhu, Duanzhuo Li, Lei Zhao, Lili Qian, Linhui Zhai, Jing Li, Han Lu, Shengnan Sun, Jiandie Lin, Yan Lu (), Xiaoying Li () and Minjia Tan ()
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Bin Liu: Fudan University
Shangwen Jiang: Chinese Academy of Sciences
Min Li: Fudan University
Xuelian Xiong: Fudan University
Mingrui Zhu: Chinese Academy of Sciences
Duanzhuo Li: Hubei Polytechnic University School of Medicine
Lei Zhao: Chinese Academy of Sciences
Lili Qian: Chinese Academy of Sciences
Linhui Zhai: Chinese Academy of Sciences
Jing Li: Shanghai Jiao Tong University
Han Lu: Shanghai Jiao-Tong University School of Medicine (SJTU-SM)
Shengnan Sun: Chinese Academy of Sciences
Jiandie Lin: University of Michigan Medical Center
Yan Lu: Fudan University
Xiaoying Li: Fudan University
Minjia Tan: Chinese Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07185-y

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