title: IL23R (Interleukin 23 Receptor) Variants Protective against Inflammatory Bowel Diseases (IBD) Display Loss of Function due to Impaired Protein Stability and Intracellular Trafficking.
abstract: Genome-wide association studies as well as murine models have shown that the interleukin 23 receptor (IL23R) pathway plays a pivotal role in chronic inflammatory diseases such as Crohn disease (CD), ulcerative colitis, psoriasis, and type 1 diabetes. Genome-wide association studies and targeted re-sequencing studies have revealed the presence of multiple potentially causal variants of the IL23R. Specifically the G149R, V362I, and R381Q IL23Rα chain variants are linked to protection against the development of Crohn disease and ulcerative colitis in humans. Moreover, the exact mechanism of action of these receptor variants has not been elucidated. We show that all three of these IL23Rα variants cause a reduction in IL23 receptor activation-mediated phosphorylation of the signal-transducing activator of transcription 3 (STAT3) and phosphorylation of signal transducing activator of transcription 4 (STAT4). The reduction in signaling is due to lower levels of cell surface receptor expression. For G149R, the receptor retention in the endoplasmic reticulum is due to an impairment of receptor maturation, whereas the R381Q and V362I variants have reduced protein stability. Finally, we demonstrate that the endogenous expression of IL23Rα protein from V362I and R381Q variants in human lymphoblastoid cell lines exhibited lower expression levels relative to susceptibility alleles. Our results suggest a convergent cause of IL23Rα variant protection against chronic inflammatory disease.
authors.affiliation: From the Department of Biochemistry, University of Montreal, Montreal, Quebec H3C 3J7, Canada, University of Ottawa, Department of Biochemistry, Microbiology, and Immunology, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Durga
authors.initials: D
authors.lastname: Sivanesan
authors.affiliation: University of Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec H1T 1C8, Canada.
authors.forename: Claudine
authors.initials: C
authors.lastname: Beauchamp
authors.affiliation: CHU Sainte-Justine, Research Centre, Montreal, Quebec H3T 1C5, Canada, and.
authors.forename: Christiane
authors.initials: C
authors.lastname: Quinou
authors.affiliation: University of Ottawa, Department of Biochemistry, Microbiology, and Immunology, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lee
authors.affiliation: Centre of Recherche Hospital Maisonneuve-Rosemont, Department of Microbiology, Infection, and Immunology, University of Montreal, Montreal, Quebec H1T 2M4, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lesage
authors.affiliation: CHU Sainte-Justine, Research Centre, Montreal, Quebec H3T 1C5, Canada, and.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
authors.affiliation: University of Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec H1T 1C8, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.affiliation: From the Department of Biochemistry, University of Montreal, Montreal, Quebec H3C 3J7, Canada, stephen.michnick@umontreal.ca.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Michnick
mesh_terms: D019943:Amino Acid Substitution; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D055550:Protein Stability; D021381:Protein Transport; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: C515500:IL23R protein, human; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human
keywords: genetic polymorphism; glycosylation; inflammatory bowel disease (IBD); interleukin 23 receptor; protein trafficking (Golgi); receptor