A novel transcript isoform of IFI16 attenuates inflammasome activation mediated by the cytosolic DNA sensor AIM2

Abstract

Upon sensing cytoplasmic dsDNA, AIM2 triggers the formation of a multiprotein complex called the inflammasome which drives proteolytic maturation of the proinflammatory cytokines, representing a critical component in host defense against pathogens. Excessive or persistent activation of AIM2 inflammasome is supposed to cause autoimmune and autoinflammatory diseases. In mice, p202, a naturally occurring dominant-negative antagonists of AIM2, acts as a brake of inflammasome-mediated inflammatory responses. However, this strategy has so far not been discovered in human since no human homolog of p202 was found. Here, we report a novel transcript isoform of human IFI16, which has a similar domain organization as mice p202. We named it as IFI16 and the original version became IFI16. Like p202, IFI16 contains two HIN domains, but lacks the pyrin domain. IFI16 is widely distributed in various human tissues and cell lines. IFI16 co-localizes with AIM2 in the cytoplasm, whereas IFI16 is predominantly restricted to the nucleus. IFI16 interacts with AIM2 and prevents ASC recruitment. IFI16 sequesters cytoplasmic dsDNA and render it unavailable for AIM2 sensing. Enforced expression of IFI16 inhibits AIM2 inflammasome activation, whereas knockdown of IFI16 augments IL-1 secretion triggered by dsDNA but not dsRNA. We therefore identified IFI16 as a functional equivalent of mice p202 that possess inhibitory effect on AIM2 inflammasome activation in the cytoplasm.