A Novel Transcript Isoform of IFI16 Attenuates Inflammasome Activation Mediated by the Cytoplasmic DNA Sensor AIM2

Abstract

Upon sensing cytoplasmic dsDNA, AIM2 triggers the formation of a multi-protein complex called the inflammasome which drives proteolytic maturation of the proinflammatory cytokines. Excessive or persistent activation of AIM2 inflammasome might cause autoimmune and autoinflammatory diseases. In mice, p202, a naturally occurring dominant-negative antagonist of AIM2, acts as a brake of inflammasomemediated proinflammatory responses. However, a similar strategy has so far not been identified in human since no human homolog of p202 was found. Here, we report a novel transcript isoform of human IFI16, which shares a similar domain architecture with mouse p202. We named it as IFI16-b and the original version became IFI16-a. Like p202, IFI16-b contains two HIN domains, but lacks the pyrin domain. IFI16-b was widely distributed in various human tissues and cell lines. IFI16-b co-localized with AIM2 in the cytoplasm, whereas IFI16-a was predominantly restricted to the nucleus. IFI16-b interacted with AIM2 and interrupted the formation of AIM2-ASC complex. IFI16-b sequestered cytoplasmic dsDNA derived from HSV1 and rendered it unavailable for AIM2 sensing. Enforced expression of IFI16-b inhibited the activation of AIM2 inflammasome, whereas knockdown of IFI16-b augmented IL-1b secretion triggered by dsDNA or DNA viruses but not dsRNA or RNA viruses. Therefore cytoplasm-localized IFI16-b was a functional equivalent of mouse p202 that exerts inhibitory effect on DNA virus-induced AIM2 inflammasome. Supported by Hong Kong Research Grants Council (C7011-15R) and Hong Kong Health and Medical Research Fund (HKM-15-M01).