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

Author

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  • Bin Liu

    (Fudan University
    Hubei Polytechnic University School of Medicine
    Chinese Academy of Sciences)

  • Shangwen Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Min Li

    (Fudan University)

  • Xuelian Xiong

    (Fudan University)

  • Mingrui Zhu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Duanzhuo Li

    (Hubei Polytechnic University School of Medicine)

  • Lei Zhao

    (Chinese Academy of Sciences)

  • Lili Qian

    (Chinese Academy of Sciences
    University of 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
    University of Chinese Academy of Sciences)

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.

Suggested Citation

  • 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 & Minjia Tan, 2018. "Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07185-y
    DOI: 10.1038/s41467-018-07185-y
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    Cited by:

    1. Dongni Shi & Xianqiu Wu & Yunting Jian & Junye Wang & Chengmei Huang & Shuang Mo & Yue Li & Fengtian Li & Chao Zhang & Dongsheng Zhang & Huizhong Zhang & Huilin Huang & Xin Chen & Y. Alan Wang & Chuyo, 2022. "USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Minxuan Xu & Jun Tan & Xin Liu & Li Han & Chenxu Ge & Yujie Zhang & Fufang Luo & Zhongqin Wang & Xiaoqin Xue & Liangyin Xiong & Xin Wang & Qinqin Zhang & Xiaoxin Wang & Qin Tian & Shuguang Zhang & Qin, 2023. "Tripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Zhen Ning & Xin Guo & Xiaolong Liu & Chang Lu & Aman Wang & Xiaolin Wang & Wen Wang & Huan Chen & Wangshu Qin & Xinyu Liu & Lina Zhou & Chi Ma & Jian Du & Zhikun Lin & Haifeng Luo & Wuxiyar Otkur & Hu, 2022. "USP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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