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

doi:10.1038/ncomms12179

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

Nat Commun. 2016 Jul 14:7:12179. doi: 10.1038/ncomms12179.

Authors

Dong-Hyun Kim¹, Sanghoon Kwon¹, Sangwon Byun¹, Zhen Xiao², Sean Park¹, Shwu-Yuan Wu³, Cheng-Ming Chiang³, Byron Kemper¹, Jongsook Kim Kemper¹

Affiliations

¹ Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
² Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
³ Simmons Comprehensive Cancer Center, Department of Biochemistry, and Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Bile Acids and Salts / metabolism*
Cell Nucleus / metabolism
Cholestasis / pathology
Disease Progression
Down-Regulation
Epigenesis, Genetic
Hep G2 Cells
Homeostasis*
Humans
Liver / metabolism
Lysine / metabolism
Male
Mice, Inbred BALB C
Models, Biological
Molecular Chaperones / chemistry
Molecular Chaperones / genetics
Molecular Chaperones / metabolism*
Mutation / genetics
Nuclear Pore Complex Proteins / chemistry
Nuclear Pore Complex Proteins / genetics
Nuclear Pore Complex Proteins / metabolism*
Phosphorylation
Phosphothreonine / metabolism
Protein Binding
Protein Transport
Receptors, Cytoplasmic and Nuclear / chemistry
Receptors, Cytoplasmic and Nuclear / metabolism*
Small Ubiquitin-Related Modifier Proteins / metabolism
Sumoylation*

Substances

Bile Acids and Salts
Molecular Chaperones
Nuclear Pore Complex Proteins
Receptors, Cytoplasmic and Nuclear
Small Ubiquitin-Related Modifier Proteins
nuclear receptor subfamily 0, group B, member 2
ran-binding protein 2
Phosphothreonine
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding