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

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Daniel B. Graham, Ariel Lefkovith, Patrick Deelen, Niek de Klein, Mukund Varma, Angela Boroughs, A. Nicole Desch, Aylwin C.Y. Ng, Gaelen Guzman, Monica Schenone, Christine P. Petersen, Atul K. Bhan, Manuel A. Rivas, Mark J. Daly, Steven A. Carr, Cisca Wijmenga, Ramnik J. Xavier
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.

Graphical abstract

Teaser

Graham et al. functionally dissect a complex genetic locus associated with inflammatory bowel disease. They find that TMEM258 is required for efficient N-linked protein glycosylation and, as such, is a central mediator of ER homeostasis in the context of intestinal inflammation.


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