Zika virus protease induces caspase-independent pyroptotic cell death by directly cleaving gasdermin D

The association of Zika virus (ZIKV) infection with a congenital malformation in fetuses, neurological, and other systemic complications in adults have brought significant global health emergency. ZIKV targets nerve cells in the brain and causes cell death, such as pyroptosis, leading to neuroinflammation. Here we described a novel mechanism of pyroptosis caused by ZIKV protease. We found that ZIKV protease directly cleaved the GSDMD into N-terminal fragment (1–249) leading to pyroptosis in a caspase-independent manner, suggesting a direct mechanism of ZIKV-induced cell death and subsequent inflammation. Our findings might shed new light to explore the pathogenesis of ZIKV infections where ZIKV protease might be a suitable target for the development of antiviral agents. •ZIKV infection induces pyroptotic cell death in both caspase-dependent and independent manners.•ZIKV protease directly cleaves the peptide bond of GSDMD between Arg249 and Ser250.•The N-terminal fragment of GSDMD results in the pore formation, leading to a caspase-independent pyroptosis.