title: SUMOylation of the farnesoid X receptor (FXR) regulates the expression of FXR target genes.
abstract: BACKGROUND
  Small ubiquitin-like modifiers (SUMO) are covalently conjugated to other proteins including nuclear receptors leading to modification of various cellular processes.
  
  
  RESULTS
  Ligand-dependent SUMOylation of farnesoid X receptor (FXR) negatively regulates the expression of its target genes.
  
  
  CONCLUSIONS
  SUMO modification attenuates the capacity of FXR to function as a transcriptional activator.
  
  
  CONCLUSIONS
  Defining post-translation modification of FXR bySUMOis important to understanding how this nuclear receptor functions in health and disease. The farnesoid X receptor (FXR) belongs to a family of ligand-activated transcription factors that regulate many aspects of metabolism including bile acid homeostasis. Here we show that FXR is covalently modified by the small ubiquitin-like modifier (Sumo1), an important regulator of cell signaling and transcription. Well conserved consensus sites at lysine 122 and 275 in the AF-1 and ligand binding domains, respectively, of FXR were subject to SUMOylation in vitro and in vivo. Chromatin immunoprecipitation (ChIP) analysis showed that Sumo1 was recruited to the bile salt export pump (BSEP), the small heterodimer partner (SHP), and the OSTα-OSTβ organic solute transporter loci in a ligand-dependent fashion. Sequential chromatin immunoprecipitation (ChIP-ReChIP) verified the concurrent binding of FXR and Sumo1 to the BSEP and SHP promoters. Overexpression of Sumo1 markedly decreased binding and/or recruitment of FXR to the BSEP and SHP promoters on ChIP-ReChIP. SUMOylation did not have an apparent effect on nuclear localization of FXR. Expression of Sumo1 markedly inhibited the ligand-dependent, transactivation of BSEP and SHP promoters by FXR/retinoid X receptor α (RXRα) in HepG2 cells. In contrast, mutations that abolished SUMOylation of FXR or siRNA knockdown of Sumo1 expression augmented the transactivation of BSEP and SHP promoters by FXR. Pathways for SUMOylation were significantly altered during obstructive cholestasis with differential Sumo1 recruitment to the promoters of FXR target genes. In conclusion, FXR is subject to SUMOylation that regulates its capacity to transactivate its target genes in normal liver and during obstructive cholestasis.
authors.affiliation: Department of Pediatrics and Children's Hospital Colorado Research Institute, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Balasubramaniyan
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Luo
authors.forename: An-Qiang
authors.initials: AQ
authors.lastname: Sun
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Suchy
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D002779:Cholestasis / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D016384:Consensus Sequence; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation; D014158:Transcription, Genetic; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D002843:Chromatin; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D025842:SUMO-1 Protein; D025841:Small Ubiquitin-Related Modifier Proteins; D000099150:Receptor, Farnesoid X-Activated; C093491:ABCB11 protein, human; C495501:SUMO1 protein, human; C117909:SUMO2 protein, human; C099713:nuclear receptor subfamily 0, group B, member 2
keywords: ABC Transporter; Bile Acid Transporters; Cholestasis; Chromatin Histone Modification; Gene Regulation; Gene Transcription; Histone Modifications; Nuclear Receptors
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