TRIM4-mediated ubiquitination of NSP2 restricts porcine reproductive and respiratory syndrome virus proliferation

Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious and virulent infectious disease caused by the porcine reproductive and respiratory syndrome virus (PRRSV), which has substantial economic losses in the pig industry worldwide, and PRRSV attenuated vaccines and inactivated vaccines do have limitations in immune protection. The discovery of new antiviral targets has become a new research field. The proteomic studies have shown that the PRRSV NSP2 protein interacts with tripartite motif protein 4 (TRIM4), but it was still unknown whether TRIM4 regulates PRRSV infections. In this study, the TRIM4 gene from Marc-145 cells was cloned, and it was proved that TRIM4 overexpression inhibits PRRSV replication, whereas TRIM4 small-interfering-RNA knockdown resulted in increased virus titers. Mechanism investigation indicated that TRIM4 inhibits PRRSV replication through ubiquitination and degradation of the NSP2 protein. Protease inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) attenuated the TRIM4-driven degradation of NSP2. Taken together, TRIM4 impairs PRRSV proliferation via ubiquitination and degradation of NSP2.