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Nature:与克罗恩病有关的又一个基因位点

来源:Nature 2008-11-14 11:11

专题:Nature报道

克罗恩病(肠道的一种慢性炎症)已被与超过30个基因位点联系起来。本期Nature上两篇论文是关于最新发现的一个位点的,这个位点是ATG16L1 (Atg16-like 1)。Atg16蛋白本身是首次在酵母中作为自噬过程的一个必要基因被发现的。自噬过程可将不想要的细胞成分清除掉,细菌感染、神经退化和肿瘤生成等发病机理都涉及这一过程。

Cadwell等人报告了Atg16L1在Paneth细胞中的独特作用。Paneth细胞是一种上皮细胞,向小肠中分泌含有抗菌肽的颗粒。Saiot发现,ATG16L1在分离的巨噬细胞和在小鼠的小肠中所发生的炎症反应中都起一定作用,是自噬机制的一个必要组成成分。这项工作表明,ATG16L1在炎症免疫反应的控制及小肠屏障的维护中发挥作用,这两个过程对于防止肠道炎症的发生都很重要。(生物谷Bioon.com)

生物谷推荐原始出处:

Nature 456, 259-263 (13 November 2008) | doi:10.1038/nature07416

A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells

Ken Cadwell1, John Y. Liu1, Sarah L. Brown1, Hiroyuki Miyoshi1, Joy Loh1, Jochen K. Lennerz1, Chieko Kishi5, Wumesh Kc1, Javier A. Carrero1, Steven Hunt2, Christian D. Stone3, Elizabeth M. Brunt1, Ramnik J. Xavier6, Barry P. Sleckman1, Ellen Li3, Noboru Mizushima5, Thaddeus S. Stappenbeck1,7 & Herbert W. Virgin IV1,4,7

1 Department of Pathology and Immunology,
2 Department of Surgery,
3 Department of Medicine,
4 Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA
5 Department of Physiology and Cell Biology, Tokyo Medical and Dental University Graduate School and Faculty of Medicine, Tokyo 113-8519, Japan
6 Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
7 These authors contributed equally to this work.

Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci1. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment3. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.

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