IL23R (Interleukin 23 Receptor) variants protective against inflammatory bowel diseases (IBD) display loss of functiondue to impaired protein stability and intracellular trafficking
Article [Version of Record]
Is part of
Journal of biological chemistry ; vol. 291, no. 16, pp. 8673-8685.Publisher(s)
ElsevierAuthor(s)
Abstract(s)
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 IL23R 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 IL23R variants cause a reduction in IL23
receptor activation-mediated phosphorylation of the signaltransducing 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 IL23R 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 IL23R variant protection
against chronic inflammatory disease.