Zika virus elicits inflammation to evade antiviral response by cleaving cGAS via NS1‐caspase‐1 axis

Viral infection triggers host innate immune responses, which primarily include the activation of type I interferon (IFN) signaling and inflammasomes. Here, we report that Zika virus (ZIKV) infection triggers NLRP3 inflammasome activation, which is further enhanced by viral non‐structural protein NS1 to benefit its replication. NS1 recruits the host deubiquitinase USP8 to cleave K11‐linked poly‐ubiquitin chains from caspase‐1 at Lys134, thus inhibiting the proteasomal degradation of caspase‐1. The enhanced stabilization of caspase‐1 by NS1 promotes the cleavage of cGAS, which recognizes mitochondrial DNA release and initiates type I IFN signaling during ZIKV infection. NLRP3 deficiency increases type I IFN production and strengthens host resistance to ZIKV in vitro and in vivo . Taken together, our work unravels a novel antagonistic mechanism employed by ZIKV to suppress host immune response by manipulating the interplay between inflammasome and type I IFN signaling, which might guide the rational design of therapeutics in the future. Synopsis Zika virus promotes NLRP3 inflammasome activation by stabilizing caspase‐1 to suppress cGAS‐mediated type I IFN signaling. The non‐structural protein NS1 enhances ZIKV‐induced NLRP3 inflammasome activation. NS1 stabilizes caspase‐1 by blocking its proteasomal degradation. NS1 recruits USP8 to cleave K11‐linked poly‐ubiquitin chains from caspase‐1 at Lys134. ZIKV enhances inflammasome activation to benefit its infection by inhibiting type I IFN signaling. NS1‐mediated stabilization of caspase‐1 promotes the cleavage of cGAS. Graphical Abstract The Zika virus promotes NLRP3 inflammasome activation by stabilizing caspase‐1 to suppress cGAS‐mediated type I IFN signaling.