Cellular Inhibitors of Apoptosis Proteins cIAP1 and cIAP2 Are Required for Efficient Caspase-1 Activation by the Inflammasome

SummaryPathogen 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.

► cIAP1/2 are required for caspase-1 activation by the inflammasome ► cIAP1, cIAP2, and TRAF2 interact with caspase-1 and direct its K63 ubiquitination ► Birc2−/− and Birc3−/− mice are resistant to inflammasome-dependent peritonitis ► Administration of IAP inhibitor blocks IL-1β production and infiltration of Gr1+ neutrophils