Crohn's disease: NOD2, autophagy and ER stress converge.
Crohn's disease: NOD2, autophagy and ER stress converge.
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作者：
Fritz T;Niederreiter L;Adolph T;Blumberg RS;Kaser A
编码细胞内模式识别受体的NOD2的多态性在迄今确定的>40个风险基因座中贡献了克罗恩病遗传风险的最大部分。自噬在针对细胞内细菌的先天免疫应答中起着重要作用。自噬基因ATG16L1和IRGM作为克罗恩病风险因素的发现使自噬成为炎症性肠病（IBD）的焦点。值得注意的是，NOD2最近被鉴定为有效的自噬诱导剂。NOD2和ATG16L1的物理相互作用似乎是细胞内病原体的自噬清除所必需的。此外，克罗恩病相关的NOD2和ATG16L1变体在诱导自噬反应方面表现出缺陷，因此预测自噬是导致克罗恩病的关键会聚机制。另一个与自噬密切相关并相互交叉调节的途径是未折叠蛋白反应（UPR），其由内质网（ER）应激诱导。参与UPR的基因（XBP1，ORMDL3）也与克罗恩病和溃疡性结肠炎有遗传相关性。此外，在宿主和微生物之间的界面处的肠上皮似乎特别受到IBD相关的自噬和UPR的亚形态功能的影响。因此，IBD的主要遗传风险因素在这些先天免疫途径上的功能趋同对宿主与微生物群的相互作用具有重要意义。此外，这些分子机制的遗传趋同可能为IBD开辟新的治疗选择，值得进一步探索。
Polymorphisms in NOD2, encoding an intracellular pattern recognition receptor, contribute the largest fraction of genetic risk for Crohn’s disease among the >40 risk loci identified so far. Autophagy plays a prominent role in the innate immune response towards intracellular bacteria. The discovery of the autophagy genes ATG16L1 and IRGM as risk factors for Crohn’s disease turned autophagy into the spotlight in inflammatory bowel disease (IBD). Remarkably, NOD2 has recently been identified as a potent autophagy inducer. A physical interaction of NOD2 and ATG16L1 appears to be required for autophagic clearance of intracellular pathogens. Moreover, Crohn’s disease-associated NOD2 and ATG16L1 variants exhibit a defect in the induction of an autophagic response and hence predict autophagy as a key converging mechanism that leads to Crohn’s disease. Another pathway that is closely intertwined with autophagy and mutually cross-regulated is the unfolded protein response (UPR), which is induced by endoplasmic reticulum (ER) stress. Genes involved in the UPR (XBP1, ORMDL3) have also been genetically associated with Crohn’s disease and ulcerative colitis. Moreover, the intestinal epithelium at the interface between host and microbe appears particularly affected by IBD-associated hypomorphic function of autophagy and the UPR. The functional convergence of main genetic risk factors for IBD on these innate immune pathways has hence important implications for the host’s interaction with the microbiota. Moreover, the genetic convergence on these molecular mechanisms may open novel therapeutic options for IBD that deserve further exploration.
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影响因子：
11.1
作者：
He C;Klionsky DJ
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