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Porcine reproductive and respiratory syndrome viru s (PRRSV) is the cause of porcine reproductive and respiratory syndrome (PRRS); a disease of pigs, which results in great economic losses in the pork industry. The non-structural protein 4 (Nsp4), a 3C-like serine protease responsible for most non-structural protein processing, plays an essential role in PRRSV infection. We used label-free quantitative proteomics to elucidate the Nsp4 interactome and SRCAP was identified as one of the interactors. SRCAP facilitated PRRSV infection by activating non-canonical Notch signaling. The ATPase I–IV domain in SRCAP and the 122 VITEA 126 in Nsp4 were identified as the interacting sites. The infection of recovered mutant rTA-12/5A ( 122 AAAAA 126 ) could not activate Notch signaling. The results indicated that 122 VITEA 126 in Nsp4 were key sites to determine the function of SRCAP and their interaction. A function of Nsp4 in activating the Notch signaling pathway was discovered. Block Notch signaling pathway could inhibit PRRSV infection both in vitro and in vivo which may lead to the development of novel therapeutic antiviral strategies. IMPORTANCE In the present study, the interactome of the NSP4 originating from PRRSV was studied and SRCAP was confirmed as one of the interactors. Mechanism study showed the interaction of Nsp4 and SRCAP was found to facilitate PRRSV infection by activating non-canonical Notch signaling. ATPase Ⅰ–Ⅳ domain in SRCAP and the 122 VITEA 126 in Nsp4 were identified as the interacting sites that demined the activating of Notch signaling. Block Notch signaling pathway could inhibit PRRSV infection in vitro and in vivo which may be a new target for antiviral drug development.
Porcine reproductive and respiratory syndrome viru s (PRRSV) is the cause of porcine reproductive and respiratory syndrome (PRRS); a disease of pigs, which results in great economic losses in the pork industry. The non-structural protein 4 (Nsp4), a 3C-like serine protease responsible for most non-structural protein processing, plays an essential role in PRRSV infection. We used label-free quantitative proteomics to elucidate the Nsp4 interactome and SRCAP was identified as one of the interactors. SRCAP facilitated PRRSV infection by activating non-canonical Notch signaling. The ATPase I–IV domain in SRCAP and the 122 VITEA 126 in Nsp4 were identified as the interacting sites. The infection of recovered mutant rTA-12/5A ( 122 AAAAA 126 ) could not activate Notch signaling. The results indicated that 122 VITEA 126 in Nsp4 were key sites to determine the function of SRCAP and their interaction. A function of Nsp4 in activating the Notch signaling pathway was discovered. Block Notch signaling pathway could inhibit PRRSV infection both in vitro and in vivo which may lead to the development of novel therapeutic antiviral strategies. IMPORTANCE In the present study, the interactome of the NSP4 originating from PRRSV was studied and SRCAP was confirmed as one of the interactors. Mechanism study showed the interaction of Nsp4 and SRCAP was found to facilitate PRRSV infection by activating non-canonical Notch signaling. ATPase Ⅰ–Ⅳ domain in SRCAP and the 122 VITEA 126 in Nsp4 were identified as the interacting sites that demined the activating of Notch signaling. Block Notch signaling pathway could inhibit PRRSV infection in vitro and in vivo which may be a new target for antiviral drug development.
Endoribonuclease (NendoU) is unique and conserved as a major genetic marker in nidoviruses that infect vertebrate hosts. Arterivirus nonstructural protein 11 (nsp11) was shown to have NendoU activity and play essential roles in the viral life cycle. Here, we report three crystal structures of porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus (EAV) nsp11 mutants. The structures of arterivirus nsp11 contain two conserved compact domains: the N-terminal domain (NTD) and C-terminal domain (CTD). The structures of PRRSV and EAV endoribonucleases are similar and conserved in the arterivirus, but they are greatly different from that of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoV), representing important human pathogens in the Nidovirales order. The catalytic center of NendoU activity is located in the CTD, where a positively charged groove is next to the key catalytic residues conserved in nidoviruses. Although the NTD is nearly identical, the catalytic region of the arterivirus nsp11 family proteins is remarkably flexible, and the oligomerization may be concentration dependent. In summary, our structures provide new insight into this key multifunctional NendoU family of proteins and lay a foundation for better understanding of the molecular mechanism and antiviral drug development.IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus are two major members of the arterivirus family. PRRSV, a leading swine pathogen, causes reproductive failure in breeding stock and respiratory tract illness in young pigs. Due to the lack of a suitable vaccine or effective drug treatment and the quick spread of these viruses, infected animals either die quickly or must be culled. PRRSV costs the swine industry around $644 million annually in the United States and almost €1.5 billion in Europe every year. To find a way to combat these viruses, we focused on the essential viral nonstructural protein 11 (nsp11). nsp11 is associated with multiple functions, such as RNA processing and suppression of the infected host innate immunity system. The three structures solved in this study provide new insight into the molecular mechanisms of this crucial protein family and will benefit the development of new treatments against these deadly viruses.
BackgroundPorcine reproductive and respiratory syndrome virus (PRRSV) is the cause of an economically important swine disease that has devastated the swine industry since the late 1980s. The aim of the present study was to investigate the interaction between reactive oxygen species (ROS) and NF-κB by PRRSV infection.ResultsWe isolated the local strain of PRRSV from southwest China, designated YN-2011, then sequenced and analyzed the genome. YN-2011 was then used to evaluate the interaction of ROS and NF-κB. In PRRSV infected MARC-145 cells, there was a time-dependent increase in ROS and Maleic Dialdehyde (MDA). Accordingly, NF-κB activation was also increased as PRRSV infection progressed. Degradation of IκB mRNA was detected late in PRRSV infection, and overexpression of the dominant negative form of IκBα significantly suppressed NF-κB induced by PRRSV.ConclusionsThe results indicate that the generation of ROS is involved in PRRSV replication and this progression is associated with the alteration in NF-κB activity induced by ROS. These results should extend our better understanding the interaction between PRRSV and host MARC-145 cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-015-0480-z) contains supplementary material, which is available to authorized users.
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