title: A CK2-RNF4 interplay coordinates non-canonical SUMOylation and degradation of nuclear receptor FXR.
abstract: Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor that plays a central role in regulating genes involved in bile acid homeostasis, and fat and glucose metabolism. Here, we demonstrate a post-translational interplay between FXR phosphorylation, SUMOylation, and ubiquitination that directs the receptor into an activation-degradation pathway in hepatocytes. We identify a non-canonical SUMOylation motif termed pSuM that conjugates SUMO2 at Lys-325 of FXR under the direct control of casein kinase 2 (CK2), which provides the required negative charge for Ubc9 and PIAS1 to perform SUMOylation, by phosphorylating Ser-327. Lys-325 SUMOylation is indispensable to the promotion of efficient ligand activation and transcriptional coactivation of FXR. Constitutive pSuM activation using a phospho-mimic Ser-327 mutant or catalytic CK2 expression strongly induces SUMO2 conjugation, which directs FXR ubiquitination and proteasome-dependent degradation. We also determine that such SUMOylation-dependent ubiquitination of FXR is mediated by the E3 ubiquitin ligase RNF4, which is required to achieve maximal induction of FXR and optimal up- or downregulation of responsive genes involved in bile acid homeostasis and liver regeneration. Our findings identify a highly regulated atypical SUMO conjugation motif that serves to coordinate FXR transcriptional competence, thereby expanding the intricate dynamics of the SUMOylation process used by incoming signals to govern metabolic gene regulation.
authors.affiliation: Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada.|Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bilodeau
authors.affiliation: Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Caron
authors.affiliation: Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada.|Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gagnon
authors.affiliation: Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada.|Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kuftedjian
authors.affiliation: Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada.|Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada.|Department of Obstetrics & Gynecology, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada.
authors.forename: André
authors.initials: A
authors.lastname: Tremblay
mesh_terms: D020816:Amino Acid Motifs; D047390:Casein Kinase II / Q000378:metabolism*; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation; D014157:Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C096916:FXR1 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C114070:RNF4 protein, human; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D012694:Serine; D047390:Casein Kinase II; D008239:Lysine
keywords: 26S proteasome; SUMOylation; bile acid; farnesoid receptor; ubiquitination