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Critical role of RanBP2-mediated SUMOylation of Small Heterodimer Partner in maintaining bile acid homeostasis

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  • Dong-Hyun Kim

    (University of Illinois at Urbana-Champaign)

  • Sanghoon Kwon

    (University of Illinois at Urbana-Champaign)

  • Sangwon Byun

    (University of Illinois at Urbana-Champaign)

  • Zhen Xiao

    (Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research)

  • Sean Park

    (University of Illinois at Urbana-Champaign)

  • Shwu-Yuan Wu

    (Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center)

  • Cheng-Ming Chiang

    (Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center)

  • Byron Kemper

    (University of Illinois at Urbana-Champaign)

  • Jongsook Kim Kemper

    (University of Illinois at Urbana-Champaign)

Abstract

Bile acids (BAs) are recently recognized signalling molecules that profoundly affect metabolism. Because of detergent-like toxicity, BA levels must be tightly regulated. An orphan nuclear receptor, Small Heterodimer Partner (SHP), plays a key role in this regulation, but how SHP senses the BA signal for feedback transcriptional responses is not clearly understood. We show an unexpected function of a nucleoporin, RanBP2, in maintaining BA homoeostasis through SUMOylation of SHP. Upon BA signalling, RanBP2 co-localizes with SHP at the nuclear envelope region and mediates SUMO2 modification at K68, which facilitates nuclear transport of SHP and its interaction with repressive histone modifiers to inhibit BA synthetic genes. Mice expressing a SUMO-defective K68R SHP mutant have increased liver BA levels, and upon BA- or drug-induced biliary insults, these mice exhibit exacerbated cholestatic pathologies. These results demonstrate a function of RanBP2-mediated SUMOylation of SHP in maintaining BA homoeostasis and protecting from the BA hepatotoxicity.

Suggested Citation

  • Dong-Hyun Kim & Sanghoon Kwon & Sangwon Byun & Zhen Xiao & Sean Park & Shwu-Yuan Wu & Cheng-Ming Chiang & Byron Kemper & Jongsook Kim Kemper, 2016. "Critical role of RanBP2-mediated SUMOylation of Small Heterodimer Partner in maintaining bile acid homeostasis," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12179
    DOI: 10.1038/ncomms12179
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    Cited by:

    1. Zhe Gong & Jinjin Zhu & Junxin Chen & Fan Feng & Haitao Zhang & Zheyuan Zhang & Chenxin Song & Kaiyu Liang & Shuhui Yang & Shunwu Fan & Xiangqian Fang & Shuying Shen, 2023. "CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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