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

Cell Rep
Authors
Keywords
Abstract

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.

Year of Publication
2016
Journal
Cell Rep
Volume
17
Issue
11
Pages
2955-2965
Date Published
2016 12 13
ISSN
2211-1247
DOI
10.1016/j.celrep.2016.11.042
PubMed ID
27974209
PubMed Central ID
PMC5661940
Links
Grant list
P30 DK043351 / DK / NIDDK NIH HHS / United States
R01 DK097485 / DK / NIDDK NIH HHS / United States
U19 AI109725 / AI / NIAID NIH HHS / United States