克羅恩?。c道的一種慢性炎癥）已被與超過30個(gè)基因位點(diǎn)聯(lián)系起來,。本期Nature上兩篇論文是關(guān)于最新發(fā)現(xiàn)的一個(gè)位點(diǎn)的,，這個(gè)位點(diǎn)是ATG16L1 (Atg16-like 1)。Atg16蛋白本身是首次在酵母中作為自噬過程的一個(gè)必要基因被發(fā)現(xiàn)的。自噬過程可將不想要的細(xì)胞成分清除掉,，細(xì)菌感染,、神經(jīng)退化和腫瘤生成等發(fā)病機(jī)理都涉及這一過程。
Cadwell等人報(bào)告了Atg16L1在Paneth細(xì)胞中的獨(dú)特作用,。Paneth細(xì)胞是一種上皮細(xì)胞,，向小腸中分泌含有抗菌肽的顆粒。Saiot發(fā)現(xiàn),，ATG16L1在分離的巨噬細(xì)胞和在小鼠的小腸中所發(fā)生的炎癥反應(yīng)中都起一定作用,，是自噬機(jī)制的一個(gè)必要組成成分。這項(xiàng)工作表明,，ATG16L1在炎癥免疫反應(yīng)的控制及小腸屏障的維護(hù)中發(fā)揮作用,，這兩個(gè)過程對(duì)于防止腸道炎癥的發(fā)生都很重要。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
