Cellular Inhibitors of Apoptosis cIAP1 and cIAP2 Are Required for Innate Immunity Signaling by the Pattern Recognition Receptors NOD1 and NOD2
Cellular Inhibitors of Apoptosis cIAP1 and cIAP2 Are Required for Innate Immunity Signaling by the Pattern Recognition Receptors NOD1 and NOD2
复制标题
DOI：
10.1016/j.immuni.2009.04.011
复制
发表时间：
2009-06-19
期刊：
影响因子：
32.4
通讯作者：
Saleh, Maya
中科院分区：
文献类型：
--
作者：
Bertrand, Mathieu J. M.;Doiron, Karine;Saleh, Maya
细胞凋亡抑制蛋白（cIAP）可以阻断细胞凋亡，但其生理功能仍在研究中。在这里，我们报告说，cIAP 1和cIAP 2是E3泛素连接酶，需要受体相互作用蛋白2（RIP 2）泛素化和核苷酸结合和寡聚化（NOD）信号。来自Birc 2（-/-）或Birc 3（-/-）小鼠的巨噬细胞，或通过RNAi去除cIAP 1或cIAP 2的结肠细胞，在NOD信号传导中有缺陷，并显示出细胞因子和趋化因子产生的急剧减弱。当用NOD激动剂攻击Birc 2（-/-）和Birc 3（-/-）小鼠时，在体内观察到这种钝化的反应。NOD 2信号传导的缺陷与克罗恩病相关，并且NOD 2信号传导的胞壁酰二肽（MDP）激活保护小鼠免受实验性结肠炎。在这里，我们表明MDP的施用保护野生型而不是Ripk 2（-/-）或Birc 3（-/-）小鼠免于结肠炎，证实了cIAP在体内NOD 2信号传导中的作用。这一发现为治疗NOD依赖性免疫和炎症疾病提供了治疗机会。
Cellular inhibitor of apoptosis proteins (cIAPs) block apoptosis, but their physiological functions are still under investigation. Here, we report that cIAP1 and cIAP2 are E3 ubiquitin ligases that are required for receptor-interacting protein 2 (RIP2) ubiquitination and for nucleotide-binding and oligomerization (NOD) signaling. Macrophages derived from Birc2(-/-) or Birc3(-/-) mice, or colonocytes depleted of cIAP1 or cIAP2 by RNAi, were defective in NOD signaling and displayed sharp attenuation of cytokine and chemokine production. This blunted response was observed in vivo when Birc2(-/-) and Birc3(-/-) mice were challenged with NOD agonists. Defects in NOD2 signaling are associated with Crohn's disease, and muramyl dipeptide (MDP) activation of NOD2 signaling protects mice from experimental colitis. Here, we show that administration of MDP protected wild-type but not Ripk2(-/-) or Birc3(-/-) mice from colitis, confirming the role of the cIAPs in NOD2 signaling in vivo. This discovery provides therapeutic opportunities in the treatment of NOD-dependent immunologic and inflammatory diseases.