TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation

• Main Authors: Graham, Daniel B. (Author), Lefkovith, Ariel (Author), Deelen, Patrick (Author), de Klein, Niek (Author), Boroughs, Angela (Author), Desch, A. Nicole (Author), Ng, Aylwin C.Y (Author), Petersen, Christine P. (Author), Bhan, Atul K. (Author), Wijmenga, Cisca (Author), Varma, Mukund Madhav (Contributor), Guzman, Gaelen Donnelly (Contributor), Schenone, Monica (Contributor), Rivas, Manuel A (Contributor), Carr, Steven A (Contributor), Xavier, Ramnik Joseph (Contributor), Daly, Mark J. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Massachusetts Institute of Technology. Department of Mechanical Engineering (Contributor), Massachusetts Institute of Technology. Department of Physics (Contributor), Daly, Mark J (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2017-04-03T14:32:23Z.
• Subjects: Article
• Online Access: Get fulltext

Summary - 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.
Leona M. and Harry B. Helmsley Charitable Trust (2014PG-IBD016)
Crohn's and Colitis Foundation of America
National Institutes of Health (U.S.) (grant DK043351)
National Institutes of Health (U.S.) (grant DK097485)