Putting a brake on inflammasome activation by reprogramming transcription from an alternative promoter: IFI16 as an example

Abstract

Inflammasome is a multiprotein complex in the cytoplasm, which not only guards against pathogens but also causes pathogenic inflammation. Inflammasome assembles around sensor proteins such as NLRP3 and AIM2, which are activated by ATP and double-stranded DNA (dsDNA), respectively. AIM2 contains an N-terminal PYD domain that recruits ASC adaptor and a C-terminal HIN domain that embraces dsDNA. Excessive activation of AIM2 inflammasome is detrimental so negative regulatory mechanisms are in place to prevent tissue damage. p202 in mice is one of 13 AIM2-homologous proteins. It contains two HIN domains without pyrin domain and functions as a dominant negative inhibitor of AIM2. It is also known as a disease locus for lupus. A human ortholog of mouse p202 has not been identified. Although there are only 4 AIM2-related proteins in humans, multiple isoforms can be generated through alternative splicing and alternative transcriptional initiation. We identified a novel human IFI16 transcript isoform named IFI16-β, which is expressed from an alternative promoter distinct to that of conventional IFI16 designated IFI16-α. IFI6-β is structurally and functionally related to mouse p202 that inhibits AIM2 inflammasome. IFI16- β transcript was ubiquitously found in multiple tissues and cells. Its expression was also induced in lupus patients and cells infected with DNA or RNA virus or treated with interferon β or phorbol ester. In contrast to nuclear IFI16-α, IFI16-β was predominantly cytoplasmic. The assembly of a functional AIM2-ASC complex was impeded by the interaction of IFI16-β with AIM2. Furthermore, cytoplasmic dsDNA was sequestered by IFI16-β and rendered inaccessible to AIM2. Activation of AIM2 inflammasome by dsDNA was augmented when IFI16-β was knocked down, but it was inhibited when IFI16-β was overexpressed. Hence, IFI16-β localized in the cytoplasm is a functional equivalent to mouse p202 that plays a dominantly inhibitory role in AIM2 inflammasome. Supported by HKRGC (T11-707/15-R).