Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 4 Cleaves Porcine DCP1a To Attenuate Its Antiviral Activity.

As one of the most significant etiological agents in pigs, porcine reproductive and respiratory syndrome virus (PRRSV) has adversely impacted the global swine industry since it was discovered in the 1980s. The mRNA-decapping enzyme 1a (DCP1a), a regulatory factor involved in removing the 5'-methylguanosine cap from eukaryotic mRNA, has recently been identified as an IFN-stimulated gene. However, the role of DCP1a in PRRSV infection is not well understood. In this study, overexpression and knockdown of porcine DCP1a (pDCP1a) showed that pDCP1a affected PRRSV infection. Interestingly, we found that PRRSV infection significantly downregulated pDCP1a expression at the protein level by cleaving pDCP1a. Furthermore, we demonstrated that PRRSV nonstructural protein 4 (nsp4), a 3C-like proteinase, is responsible for pDCP1a cleavage, and the cleaved site is at glutamic acid 238 (E238) of pDCP1a. The mutant pDCP1a-E238A, which cannot be cleaved by nsp4, showed higher anti-PRRSV activity, and the antiviral effects of two cleavage products (pDCP1a1-238 and pDCP1a239-580) were significantly decreased compared with wild type pDCP1a. Unexpectedly, PRRSV infection or overexpression of nsp4 did not cleave monkey DCP1a, and monkey DCP1a showed a higher anti-PRRSV activity than pDCP1a. Taken together, this study reveals a new strategy evolved by PRRSV to dampen the host defense, complementing the known PRRSV-mediated immune evasion mechanisms.