4.6 Article

β-Arrestin2 encourages inflammation-induced epithelial apoptosis through ER stress/PUMA in colitis

期刊

MUCOSAL IMMUNOLOGY
卷 8, 期 3, 页码 683-695

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NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2014.104

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资金

  1. Major Projects Incubator Program of the National Key Basic Research Program of China [2012CB526700]
  2. National Natural Science Foundation of China [81370511]
  3. Natural Science Foundation of Guangdong Province [52011020002348]
  4. International Cooperative Innovative Platform of Guangdong Province Universities and Colleges [gjhz1101]
  5. Projects of Guangzhou City International Cooperation [2012J5100017]

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beta-Arrestins (beta-arrs) are regulators and mediators of G protein-coupled receptor signaling, and accumulating evidence suggests that they are functionally involved in inflammation and autoimmune diseases. However, the effect of beta-arrs is unclear in inflammatory bowel disease (IBD), and the role of beta-arr2 is unknown in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study is to investigate whether beta-arr2 encourages inflammation-induced epithelial apoptosis through endoplasmic reticulum (ER) stress/p53-upregulated modulator of apoptosis (PUMA) in colitis. In the present study, the results showed that beta-arr2 was increased in specimens from patients with UC or CD. Furthermore, a beta-arr2 deficiency significantly repressed intestinal inflammation, ameliorated colitis, and alleviated mucosal apoptosis in mice. In addition, the targeted deletion of beta-arr2 depressed ER stress, inhibited PUMA, and downregulated PUMA-mediated mitochondrial apoptotic signaling in colitis. beta-Arr2, an important modulator of G protein-coupled receptor function, binds elF2 alpha to activate ER stress signaling. Furthermore, the knockdown of PUMA dramatically prevented beta-arr2-induced apoptosis via alleviating ER stress in vitro. The results suggest that beta-arr2 encourages inflammationinduced epithelial apoptosis through ER stress/PUMA in colitis and that beta-arr2 is a potential therapeutic target for colitis.

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