The non-structural protein of SFTSV activates NLRP1 and CARD8 inflammasome through disrupting the DPP9-mediated ternary complex

Inflammasomes function as immune-signaling platforms that were assembled following detection of pathogens. NLRP1 and CARD8 are related inflammasomes that use their C-terminal (CT) fragments containing a Caspase recruitment domain (CARD) and the UPA domain to initiate the inflammasome. At rest, dipeptidyl peptidases 8 and 9 (DPP8/9) inhibit inflammatory CT by interacting with the function-to-find domain (FIIND) of NLRP1/CARD8 and forming an inhibitory NLRP1/CARD8-DPP9 ternary complex consisting of DPP9, full-length NLRP1/CARD8, and NLRP1/CARD8 CT. However, the specific triggers of NLRP1 and CARD8 have not yet been fully identified. Here, we report that a tick-borne bunyavirus SFTSV Infection activates the NLRP1 inflammasome in primary keratinocytes and the CARD8 inflammasome in macrophages in a similar manner by targeting the ternary inhibitory complex, respectively. Mechanistically, SFTSV NSs interact with NLRP1 and CARD8 via their FIIND domains, suggesting that DPP8/9 are likely to compete for binding; on the Other hand, NSs promote the degradation of DPP8 and DPP9. Both contribute to more efficient destabilization of the DPP8/9 ternary complex and release the activated CT. Moreover, CARD8 deletion promotes SFTSV replication. In conclusion, we found a novel mechanism of viral protein activation of NLRP1 and CARD8 by disrupting the DPP9-binding checkpoint.