Inhibition of AIM2 inflammasome activation by a novel transcript isoform of IFI16

Mouse p202 is a disease locus for lupus and a dominant-negative inhibitor of AIM2 inflammasome activation. A human homolog of p202 has not been identified so far. Here, we report a novel transcript isoform of human IFI16-designated IFI16-theta, which has a domain architecture similar to that of mouse p202. Like p202, IFI16-beta contains two HIN domains, but lacks the pyrin domain. IFI16-beta is ubiquitously expressed in various human tissues and cells. Its mRNA levels are also elevated in leukocytes of patients with lupus, virus-infected cells, and cells treated with interferon- or phorbol ester. IFI16-beta co-localizes with AIM2 in the cytoplasm, whereas IFI16-alpha is predominantly found in the nucleus. IFI16-beta interacts with AIM2 to impede the formation of a functional AIM2-ASC complex. In addition, IFI16-beta sequesters cytoplasmic dsDNA and renders it unavailable for AIM2 sensing. Enforced expression of IFI16-beta inhibits the activation of AIM2 inflammasome, whereas knockdown of IFI16-beta augments interleukin-1 secretion triggered by dsDNA but not dsRNA. Thus, cytoplasm-localized IFI16-beta is functionally equivalent to mouse p202 that exerts an inhibitory effect on AIM2 inflammasome.