Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3G 0B1, Canada.
Immunity. 2011 Dec 23;35(6):897-907. doi: 10.1016/j.immuni.2011.10.016.
Pathogen and danger recognition by the inflammasome activates inflammatory caspases that mediate inflammation and cell death. The cellular inhibitor of apoptosis proteins (cIAPs) function in apoptosis and innate immunity, but their role in modulating the inflammasome and the inflammatory caspases is unknown. Here we report that the cIAPs are critical effectors of the inflammasome and are required for efficient caspase-1 activation. cIAP1, cIAP2, and the adaptor protein TRAF2 interacted with caspase-1-containing complexes and mediated the activating nondegradative K63-linked polyubiquitination of caspase-1. Deficiency in cIAP1 (encoded by Birc2) or cIAP2 (Birc3) impaired caspase-1 activation after spontaneous or agonist-induced inflammasome assembly, and Birc2(-/-) or Birc3(-/-) mice or mice administered with an IAP antagonist had a dampened response to inflammasome agonists and were resistant to peritonitis. Our results describe a role for the cIAPs in innate immunity and further demonstrate the evolutionary conservation between cell death and inflammation mechanisms.
病原体和危险识别物被炎症小体激活，从而激活炎症半胱天冬酶，介导炎症和细胞死亡。细胞凋亡抑制蛋白 (cIAPs) 在细胞凋亡和先天免疫中发挥作用，但它们在调节炎症小体和炎症半胱天冬酶方面的作用尚不清楚。在这里，我们报告 cIAPs 是炎症小体的关键效应物，是有效 caspase-1 激活所必需的。cIAP1、cIAP2 和衔接蛋白 TRAF2 与包含 caspase-1 的复合物相互作用，并介导 caspase-1 的激活非降解性 K63 连接多泛素化。cIAP1（由 Birc2 编码）或 cIAP2（Birc3）缺失会损害自发或激动剂诱导的炎症小体组装后 caspase-1 的激活，并且 Birc2(-/-) 或 Birc3(-/-) 小鼠或给予 IAP 拮抗剂的小鼠对炎症小体激动剂的反应减弱，并且对腹膜炎有抵抗力。我们的研究结果描述了 cIAPs 在先天免疫中的作用，并进一步证明了细胞死亡和炎症机制之间的进化保守性。
