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.


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.

MeSH terms

  • Animals
  • Apoptosis
  • Disease Models, Animal
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology
  • Endoplasmic Reticulum Stress / genetics
  • Glycosylation
  • Hexosyltransferases / genetics*
  • Hexosyltransferases / metabolism
  • Humans
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / pathology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Intestines / pathology
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice


  • Membrane Proteins
  • TMEM258 protein, mouse
  • Hexosyltransferases
  • dolichyl-diphosphooligosaccharide - protein glycotransferase