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

Abstract

<p id="d4726046e352">Viral infection triggers host innate immune responses, which primarily include the activation of type I interferon ( <span style="fixed-case">IFN</span>) signaling and inflammasomes. Here, we report that Zika virus ( <span style="fixed-case">ZIKV</span>) infection triggers <span style="fixed-case">NLRP</span>3 inflammasome activation, which is further enhanced by viral non‐structural protein <span style="fixed-case">NS</span>1 to benefit its replication. <span style="fixed-case">NS</span>1 recruits the host deubiquitinase <span style="fixed-case">USP</span>8 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 <span style="fixed-case">NS</span>1 promotes the cleavage of <span style="fixed-case">cGAS</span>, which recognizes mitochondrial <span style="fixed-case">DNA</span> release and initiates type I <span style="fixed-case">IFN</span> signaling during <span style="fixed-case">ZIKV</span> infection. <span style="fixed-case">NLRP</span>3 deficiency increases type I <span style="fixed-case">IFN</span> production and strengthens host resistance to <span style="fixed-case">ZIKV</span> <i>in vitro</i> and <i>in vivo</i>. Taken together, our work unravels a novel antagonistic mechanism employed by <span style="fixed-case">ZIKV</span> to suppress host immune response by manipulating the interplay between inflammasome and type I <span style="fixed-case">IFN</span> signaling, which might guide the rational design of therapeutics in the future. </p>