IL23R (Interleukin 23 Receptor) Variants Protective against Inflammatory Bowel Diseases (IBD) Display Loss of Function due to Impaired Protein Stability and Intracellular Trafficking

• Published in: The Journal of biological chemistry Vol. 291; no. 16; pp. 8673 - 8685
• Main Authors: Sivanesan, Durga, Beauchamp, Claudine, Quinou, Christiane, Lee, Jonathan, Lesage, Sylvie, Chemtob, Sylvain, Rioux, John D., Michnick, Stephen W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.04.2016; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Substitution; genetic polymorphism; glycosylation; HEK293 Cells; HeLa Cells; Humans; Immunology; inflammatory bowel disease (IBD); Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - metabolism; Inflammatory Bowel Diseases - pathology; interleukin 23 receptor; Mutation, Missense; Protein Stability; protein trafficking (Golgi); Protein Transport; receptor; Receptors, Interleukin - genetics; Receptors, Interleukin - metabolism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; STAT4 Transcription Factor - genetics; STAT4 Transcription Factor - metabolism; glycosylation; receptor; interleukin 23 receptor; inflammatory bowel disease (IBD); genetic polymorphism; protein trafficking (Golgi)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.715870

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.