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

  • Cell Rep. 2016 Dec 13;17(11):2955-2965. doi: 10.1016/j.celrep.2016.11.042.
Daniel B Graham  1 ,  Ariel Lefkovith  2 ,  Patrick Deelen  3 ,  Niek de Klein  3 ,  Mukund Varma  2 ,  Angela Boroughs  4 ,  A Nicole Desch  2 ,  Aylwin C Y Ng  5 ,  Gaelen Guzman  2 ,  Monica Schenone  2 ,  Christine P Petersen  2 ,  Atul K Bhan  6 ,  Manuel A Rivas  2 ,  Mark J Daly  7 ,  Steven A Carr  2 ,  Cisca Wijmenga  3 ,  Ramnik J Xavier  8
Affiliations
  • 1. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].
  • 2. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 3. Department of Genetics, Genomics Coordination Center, University Medical Center Groningen, University Medical Center Groningen, 9713 EX Groningen, the Netherlands.
  • 4. Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 5. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 6. Pathology Department and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 7. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 8. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].
PMID: 27974209 DOI: 10.1016/j.celrep.2016.11.042
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.