PRRSV Nsp11 antagonizes host antiviral immune response by reducing OAS1 and RNase L expressions

Porcine reproductive and respiratory syndrome virus (PRRSV) is the pathogen of porcine reproductive and respiratory syndrome (PRRS) which is an important viral infectious disease. PRRSV is a positive-sense single-stranded RNA virus and causes serious economic losses to the pig industry worldwide. The oligoadenylate synthesis (OAS) /Ribonuclease L (RNase L) pathway plays a key role in host innate immune response to inhibit RNA virus infection. However, whether PRRSV proteins inhibit the activation of the OAS/RNase L pathway is less well understood. In this study, we first found that the nonstructural protein (Nsp) 11 could significantly decrease OAS1 and RNase L expression and inhibit poly (I: C)-mediated ribosomal RNA (rRNA) degradation and apoptosis by agarose gel electrophoresis and TUNEL assay, suggesting that Nsp11 decreased activation of the OAS/RNase L pathway. Western blotting showed that the PRRSV infection or Nsp11 overexpression reduced OAS1 and RNase L expressions in an endoribonuclease-dependent manner. However, the proteasome and autophagy systems did not influence protein levels of OAS1 and RNase L. These results suggest that Nsp11 does not directly regulate the protein levels of OAS1 and RNase L. Thus, we detected the mRNA levels of OAS1 and RNase L in Nsp11 overexpressed cells. The real-time PCR analysis showed that Nsp11 decreased the mRNA levels of OAS1 and RNase L in an endoribonuclease-dependent manner. Meanwhile, Baf A1 could rescue Nsp11-induced reduction of OAS1 and RNase L mRNA. It is likely that PRRSV Nsp11 inhibits activation of OAS/RNase L pathway by decreasing mRNA levels of OAS1 and RNase L. Our findings reveal that PRRSV Nsp11 decreases the protein level of OAS1 and RNase L to inhibit the activation of OAS/RNase L pathway and promote PRRSV replication, suggesting a potential mechanism for viral evasion of host innate immunity in an autophagy-dependent manner. Taken together, the endoribonuclease activity of PRRSV Nsp11 antagonizes the activation of the OAS/RNase L pathway to promote PRRSV replication. Our results demonstrate a novel mechanism that Nsp11 inhibits the antiviral function of the OAS/RNase L pathway, which probably leads to persistent PRRSV infection.