title: Critical role of RanBP2-mediated SUMOylation of Small Heterodimer Partner in maintaining bile acid homeostasis.
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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Sanghoon
authors.initials: S
authors.lastname: Kwon
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Sangwon
authors.initials: S
authors.lastname: Byun
authors.affiliation: Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Park
authors.affiliation: Simmons Comprehensive Cancer Center, Department of Biochemistry, and Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Shwu-Yuan
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Simmons Comprehensive Cancer Center, Department of Biochemistry, and Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Kemper
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Jongsook Kim
authors.initials: JK
authors.lastname: Kemper
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002779:Cholestasis / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D058207:Sumoylation
chemical_list: D001647:Bile Acids and Salts; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D025841:Small Ubiquitin-Related Modifier Proteins; C099713:nuclear receptor subfamily 0, group B, member 2; C094493:ran-binding protein 2; D010769:Phosphothreonine; D008239:Lysine