A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.
A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.
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DOI：
10.1038/nature07416
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发表时间：
2008-11-13
期刊：
影响因子：
64.8
通讯作者：
Virgin, Herbert W.
中科院分区：
文献类型：
--
作者：
Cadwell, Ken;Liu, John Y.;Brown, Sarah L.;Miyoshi, Hiroyuki;Loh, Joy;Lennerz, Jochen K.;Kishi, Chieko;Kc, Wumesh;Carrero, Javier A.;Hunt, Steven;Stone, Christian D.;Brunt, Elizabeth M.;Xavier, Ramnik J.;Sleckman, Barry P.;Li, Ellen;Mizushima, Noboru;Stappenbeck, Thaddeus S.;Virgin, Herbert W.
克罗恩病(CD)是一种累及小肠的复杂炎症性疾病，其易感性由多达32个基因座控制。一个Cd风险等位基因在ATG16L1，这是一个与基本酵母自噬基因ATG16同源的基因。目前尚不清楚Atg16L1或自噬在肠道生物学或CD发病机制中的作用。为了解决这些问题，我们产生并表征了Atg16L1蛋白表达低下的小鼠，并通过分析我们从携带ATG16L1 CD风险等位基因的CD患者那里收集的肠道组织来验证基于这些小鼠的研究得出的结论。我们证明了Atg16L1是一种真正的自噬蛋白。在回肠上皮内，Atg16L1和第二个必需的自噬蛋白ATG5对Paneth细胞的生物学有选择性地重要，Paneth细胞是一种特殊的上皮细胞，其部分功能是通过分泌含有抗菌肽和其他改变肠道环境的蛋白质的颗粒内容物来发挥作用。ATG16L1和ATG5缺陷的Paneth细胞在颗粒吐出途径中表现出显著的异常。此外，转录分析显示，Atg16L1缺陷的Paneth细胞特有的功能意外增加，包括参与PPAR信号和脂肪代谢的基因、急性时相反应物以及两种已知直接影响肠道损伤反应的脂肪细胞因子瘦素和脂联素的表达增加。重要的是，ATG16L1 CD风险等位基因纯合的CD患者表现出与自噬蛋白缺陷小鼠相似的潘氏细胞颗粒异常，并表达增加的瘦素蛋白水平。因此，Atg16L1，以及可能的自噬过程，通过对Paneth细胞的细胞生物学和特殊调节特性的选择性影响，在小鼠和CD患者的肠道上皮细胞中发挥作用。
Susceptibility to Crohn's disease (CD), a complex inflammatory disease involving the small intestine, is controlled by up to 32 loci. One CD risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16. It is not known how Atg16L1 or autophagy contributes to intestinal biology or CD pathogenesis. To address these questions we generated and characterized mice that are hypomorphic for Atg16L1 protein expression, and validated conclusions based on studies in these mice by analyzing intestinal tissues that we collected from CD patients carrying the CD risk allele of ATG16L1. 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 which functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. Atg16L1 and Atg5-deficient Paneth cells exhibited striking 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 PPAR signaling and lipid metabolism, acute phase reactants, as well as two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, CD patients homozygous for the ATG16L1 CD 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 likely the process of autophagy, play their role within the intestinal epithelium of mice and CD patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.
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DOI：
10.1084/jem.20061303
发表时间：
2007-01-22
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pua HH;Dzhagalov I;Chuck M;Mizushima N;He YW
通讯作者：
He YW
影响因子：
30.8
作者：
Hampe, Jochen;Franke, Andre;Schreiber, Stefan
通讯作者：
Schreiber, Stefan
影响因子：
56.9
作者：
Duerr, Richard H.;Taylor, Kent D.;Cho, Judy H.
通讯作者：
Cho, Judy H.
影响因子：
4
作者：
Mizushima, N;Kuma, A;Yoshimori, T
通讯作者：
Yoshimori, T
DOI：
10.1073/pnas.0405979102
发表时间：
2005-01-04
影响因子：
11.1
作者：
Pull, SL;Doherty, JM;Stappenbeck, TS
通讯作者：
Stappenbeck, TS