PMID- 29899101 OWN - NLM STAT- MEDLINE DCOM- 20180817 LR - 20211204 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 92 IP - 16 DP - 2018 Aug 15 TI - Porcine Reproductive and Respiratory Syndrome Virus Infection Induces both eIF2alpha Phosphorylation-Dependent and -Independent Host Translation Shutoff. LID - 10.1128/JVI.00600-18 [doi] LID - e00600-18 AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has caused tremendous economic losses in the global swine industry since it was discovered in the late 1980s. Inducing host translation shutoff is a strategy used by many viruses to optimize their replication and spread. Here, we demonstrate that PRRSV infection causes host translation suppression, which is strongly dependent on viral replication. By screening PRRSV-encoded nonstructural proteins (nsps), we found that nsp2 participates in the induction of host translation shutoff and that its transmembrane (TM) domain is required for this process. nsp2-induced translation suppression is independent of protein degradation pathways and the phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha). However, the overexpression of nsp2 or its TM domain significantly attenuated the mammalian target of rapamycin (mTOR) signaling pathway, an alternative pathway for modulating host gene expression. PRRSV infection also attenuated the mTOR signaling pathway, and PRRSV-induced host translation shutoff could be partly reversed when the attenuated mTOR phosphorylation was reactivated by an activator of the mTOR pathway. PRRSV infection still negatively regulated the host translation when the effects of eIF2alpha phosphorylation were completely reversed. Taken together, our results demonstrate that PRRSV infection induces host translation shutoff and that nsp2 is associated with this process. Both eIF2alpha phosphorylation and the attenuation of the mTOR signaling pathway contribute to PRRSV-induced host translation arrest.IMPORTANCE Viruses are obligate parasites, and the production of progeny viruses relies strictly on the host translation machinery. Therefore, the efficient modulation of host mRNA translation benefits viral replication, spread, and evolution. In this study, we provide evidence that porcine reproductive and respiratory syndrome virus (PRRSV) infection induces host translation shutoff and that the viral nonstructural protein nsp2 is associated with this process. Many viruses induce host translation shutoff by phosphorylating eukaryotic initiation factor 2alpha (eIF2alpha). However, PRRSV nsp2 does not induce eIF2alpha phosphorylation but attenuates the mTOR signaling pathway, another pathway regulating the host cell translational machinery. We also found that PRRSV-induced host translation shutoff was partly reversed by eliminating the effects of eIF2alpha phosphorylation or reactivating the mTOR pathway, indicating that PRRSV infection induces both eIF2alpha phosphorylation-dependent and -independent host translation shutoff. CI - Copyright (c) 2018 American Society for Microbiology. FAU - Li, Yang AU - Li Y AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China. AD - The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China. FAU - Fang, Liurong AU - Fang L AUID- ORCID: 0000-0003-1406-6409 AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China fanglr@mail.hzau.edu.cn vet@mail.hzau.edu.cn. AD - The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China. FAU - Zhou, Yanrong AU - Zhou Y AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China. AD - The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China. FAU - Tao, Ran AU - Tao R AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China. AD - The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China. FAU - Wang, Dang AU - Wang D AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China. AD - The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China. FAU - Xiao, Shaobo AU - Xiao S AUID- ORCID: 0000-0003-0023-9188 AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China fanglr@mail.hzau.edu.cn vet@mail.hzau.edu.cn. AD - The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180731 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Eukaryotic Initiation Factor-2) RN - 0 (Viral Nonstructural Proteins) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Cell Line MH - Eukaryotic Initiation Factor-2/*metabolism MH - *Host-Pathogen Interactions MH - Phosphorylation MH - Porcine respiratory and reproductive syndrome virus/*physiology MH - *Protein Biosynthesis MH - *Protein Processing, Post-Translational MH - Signal Transduction MH - Swine MH - TOR Serine-Threonine Kinases/metabolism MH - Viral Nonstructural Proteins/*metabolism MH - *Virus Replication PMC - PMC6069200 OTO - NOTNLM OT - host translation shutoff OT - nonstructural protein 2 (nsp2) OT - porcine reproductive and respiratory syndrome virus EDAT- 2018/06/15 06:00 MHDA- 2018/08/18 06:00 PMCR- 2019/01/31 CRDT- 2018/06/15 06:00 PHST- 2018/04/09 00:00 [received] PHST- 2018/05/25 00:00 [accepted] PHST- 2018/06/15 06:00 [pubmed] PHST- 2018/08/18 06:00 [medline] PHST- 2018/06/15 06:00 [entrez] PHST- 2019/01/31 00:00 [pmc-release] AID - JVI.00600-18 [pii] AID - 00600-18 [pii] AID - 10.1128/JVI.00600-18 [doi] PST - epublish SO - J Virol. 2018 Jul 31;92(16):e00600-18. doi: 10.1128/JVI.00600-18. Print 2018 Aug 15.