Common carp USP30s restrict SVCV replication by attenuating mitophagy

As a selective autophagic process, mitophagy is deeply involved in antiviral immunity by eliminating damaged mitochondria and requires the participation of various enzymes. Among these, the deubiquitinating enzyme USP30 is known to regulate mitophagy in mammals, yet its function in teleost antiviral defense remains entirely unexplored. In this study, we identified two USP30 homologs from the common carp (Cyprinus carpio), CcUSP30-A and CcUSP30-B, both containing a conserved USP domain and the atypical catalytic triad (Cys73, His445, Ser470). In vitro, spring viremia of carp virus (SVCV) infection induced PINK1-Parkin-dependent mitophagy that was subsequently exploited to promote viral replication. Overexpression of CcUSP30-A and CcUSP30-B significantly upregulated mitochondrial protein levels, reduced SVCV-induced mitophagy, and restricted SVCV replication. Notably, CcUSP30-B displayed stronger anti-mitophagy and anti-SVCV activities than CcUSP30-A. These findings demonstrate that CcUSP30s antagonize the PINK1-Parkin pathway, thereby counteracting excessive SVCV-induced mitophagy and ultimately limiting viral replication. This study provides the first evidence that USP30 acts as an antiviral regulator by preserving mitochondrial integrity in teleosts, and it may serve as a promising target for a novel strategy to control SVCV infection in aquaculture.