Swine NONO promotes IRF3-mediated antiviral immune response by Detecting PRRSV N protein

Abstract

Non-POU domain-containing octamer-binding protein (NONO) is a multi-functional nuclear protein which belongs to the Drosophila behavior/human splicing (DBHS) protein family. NONO is known to regulate multiple important biological processes including host antiviral immune response. However, whether NONO can inhibit porcine reproductive and respiratory syndrome virus (PRRSV) replication is less well understood. In this study, we demonstrated that swine NONO (sNONO) inhibited PRRSV replication, via increasing expression of IFN-beta, whereas NONO knockdown or knockout in PAM-KNU cells was more susceptible to PRRSV infection. As an IRF3 positive regulation factor, NONO promoted IFN-beta expression by enhancing activation of IRF3. During PRRSV infection, NONO further up-regulated IRF3-mediated IFN-beta expression by interacting with PRRSV N protein. Mechanistically, NONO functioned as a scaffold protein to detect PRRSV N protein and formed N-NONO-IRF3 complex in the nucleus. Interestingly, it was found that the NONO protein reversed the inhibitory effect of PRRSV N protein on type I IFN signaling pathway. Taken together, our study provides a novel mechanism for NONO to increase the IRF3-mediated IFN-beta activation by interacting with the viral N protein to inhibit PRRSV infection. Porcine reproductive and respiratory syndrome (PRRS), which is caused by porcine reproductive and respiratory syndrome virus (PRRSV), is a highly infectious disease and leads to huge economic losses to the global swine industry. Here, we reported that Non-POU domain-containing octamer-binding protein (NONO) significantly inhibited PRRSV replication and increased the expression of IFN-beta. We found that NONO positively regulated IFN-beta signaling pathway by targeting IRF3 and interacted with PRRSV N protein to promote activation of IFN-beta, which reversed the inhibitory effect of PRRSV N protein on type I IFN signaling. We also found that NONO acted as a bridge to recruit PRRSV N and IRF3 to form N-NONO-IRF3 complex and enhanced activation of IFN-beta signaling. Our study uncovers a novel mechanism for NONO to exert antiviral response through interacting with PRRSV N protein and IRF3 to inhibit PRRSV replication.