Coronavirus Nsp5‑mediated dual‑site cleavage of GSDMA modifies its antiviral and proinflammatory functions.

Although Gasdermin A (GSDMA) drives inflammation by inducing pyroptosis, its specific role in antiviral defense remains unclear. Here we identify GSDMA as an immunomodulatory protein activated in response to coronavirus (CoV) infection. Specifically, CoV-encoded protease nsp5 cleaves GSDMA at two conserved glutamine sites, Q247 and Q187. Cleavage at Q247 liberates an active N-terminal fragment (GSDMA_1-247) that triggers pyroptosis, promotes inflammation, and restricts viral replication. In contrast, cleavage at the alternative site Q187 attenuates this function. Using Gsdma-/- mice, we show that GSDMA deficiency increases viral loads but reduces inflammation, tissue damage, and mortality upon infection. These findings suggest that disease severity is driven more by inflammation than by viral load. Our findings reveal a novel mechanism of antiviral immunity and inflammatory regulation via CoV nsp5-mediated dual cleavage of GSDMA, highlighting a potential target for combined antiviral and anti-inflammatory therapies.