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, Jongsook Kim Kemper

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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.

Original languageEnglish (US)
Article number12179
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Jul 14 2016

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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