TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation.
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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
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Journal | Cell Rep
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Volume | 17
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Issue | 11
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Pages | 2955-2965
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Date Published | 2016 12 13
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ISSN | 2211-1247
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DOI | 10.1016/j.celrep.2016.11.042
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PubMed ID | 27974209
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PubMed Central ID | PMC5661940
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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
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