Graham Daniel B, Lefkovith Ariel, Deelen Patrick, de Klein Niek, Varma Mukund, Boroughs Angela, Desch A Nicole, Ng Aylwin C Y, Guzman Gaelen, Schenone Monica, Petersen Christine P, Bhan Atul K, Rivas Manuel A, Daly Mark J, Carr Steven A, Wijmenga Cisca, Xavier Ramnik J
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.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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.
群体水平的基因研究为疾病发病机制提供了重要见解；然而，许多与复杂遗传性疾病相关的基因座包含众多基因，且无法明确确定表型关联。特别是，11号染色体上一个基因密集的基因座（61.5 - 61.65 Mb）与炎症性肠病、类风湿性关节炎和冠状动脉疾病有关。在此，我们确定该基因座内的TMEM258是肠道炎症的核心调节因子。引人注目的是，Tmem258单倍体不足的小鼠在结肠炎模型中表现出严重的肠道炎症。在机制层面，我们证明TMEM258是寡糖基转移酶复合物的必需成分，对N-连接蛋白糖基化至关重要。因此，结肠类器官中Tmem258的纯合缺失导致未解决的内质网（ER）应激，最终导致细胞凋亡。总体而言，我们的结果表明TMEM258是内质网质量控制和肠道稳态的核心介质。
