CcFTR54 suppresses SVCV replication by promoting NBR1-mediated autophagic degradation of P protein

The tripartite motif-containing (TRIM) protein family is crucial for antiviral innate immunity. In teleost, finTRIM proteins (FTRs) represent a fish-specific TRIM subfamily that underwent extensive lineage-specific expansion. Nevertheless, the biological roles of many FTR members have yet to be fully deciphered. Here, we identified common carp finTRIM54 (CcFTR54) as potent restriction factor against spring viremia of carp virus (SVCV) infection by targeting the viral phosphoprotein (P). CcFTR54 overexpression significantly rescued the type I interferon (IFN-I) signaling from SVCV P-mediated suppression. Mechanistic investigations revealed that CcFTR54 directly bond to P protein via its PRY/SPRY domain, enhancing the recruitment of the cargo receptor NBR1 to the P protein. Consequently, NBR1 deficiency substantially attenuated both CcFTR54-mediated P protein degradation and its antiviral efficacy. Furthermore, CcFTR54 catalyzes K6- and K33-linked ubiquitination of P protein at K205, a site crucial for SVCV replication. Together, our findings unveil a novel mechanism where CcFTR54 restricts SVCV replication via NBR1-dependent selective autophagic degradation of the viral P protein, thereby broadening our insights into finTRIM-mediated antiviral immunity in teleosts.