|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Graham, DB, Lefkovith, A, Deelen, P, de Klein, N, Varma, M, Boroughs, A, A Desch, N, C Y Ng, A, Guzman, G, Schenone, M, Petersen, CP, Bhan, AK, Rivas, MA, Daly, MJ, Carr, SA, Wijmenga, C, Xavier, RJ|
|Date Published||2016 Dec 13|
Significant insights into disease pathogenesis have been gleaned from population-level genetic studies; however, many loci associated with complex genetic disease contain numerous genes, and phenotypic associations cannot be assigned unequivocally. In particular, a gene-dense locus on chromosome 11 (61.5-61.65 Mb) has been associated with inflammatory bowel disease, rheumatoid arthritis, and coronary artery disease. Here, we identify TMEM258 within this locus as a central regulator of intestinal inflammation. Strikingly, Tmem258 haploinsufficient mice exhibit severe intestinal inflammation in a model of colitis. At the mechanistic level, we demonstrate that TMEM258 is a required component of the oligosaccharyltransferase complex and is essential for N-linked protein glycosylation. Consequently, homozygous deficiency of Tmem258 in colonic organoids results in unresolved endoplasmic reticulum (ER) stress culminating in apoptosis. Collectively, our results demonstrate that TMEM258 is a central mediator of ER quality control and intestinal homeostasis.
|Alternate Journal||Cell Rep|