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

Dong-Hyun Kim, Sanghoon Kwon, Sangwon Byun, Zhen Xiao, Sean Park, Shwu-Yuan Wu, Cheng-Ming Chiang, Byron Kemper and Jongsook Kim Kemper ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12179

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