TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation
Author(s)Graham, Daniel B.; Lefkovith, Ariel; Deelen, Patrick; de Klein, Niek; Boroughs, Angela; Desch, A. Nicole; Ng, Aylwin C.Y.; Petersen, Christine P.; Bhan, Atul K.; Wijmenga, Cisca; Varma, Mukund Madhav; Guzman, Gaelen Donnelly; Schenone, Monica; Rivas, Manuel A; Daly, Mark J; Carr, Steven A; Xavier, Ramnik Joseph; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Mechanical Engineering; Massachusetts Institute of Technology. Department of Physics
Graham, Daniel B., Ariel Lefkovith, Patrick Deelen, Niek de Klein, Mukund Varma, Angela Boroughs, A. Nicole Desch, et al. “TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation.” Cell Reports 17, no. 11 (December 2016): 2955–2965.
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