PMID- 27881658 OWN - NLM STAT- MEDLINE DCOM- 20170515 LR - 20220408 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 91 IP - 3 DP - 2017 Feb 1 TI - Porcine Reproductive and Respiratory Syndrome Virus Antagonizes JAK/STAT3 Signaling via nsp5, Which Induces STAT3 Degradation. LID - 10.1128/JVI.02087-16 [doi] LID - e02087-16 AB - Signal transducer and activator of transcription 3 (STAT3) is a pleiotropic signaling mediator of many cytokines, including interleukin-6 (IL-6) and IL-10. STAT3 is known to play critical roles in cell growth, proliferation, differentiation, immunity and inflammatory responses. The objective of this study was to determine the effect of porcine reproductive and respiratory syndrome virus (PRRSV) infection on the STAT3 signaling since PRRSV induces a weak protective immune response in host animals. We report here that PRRSV infection of MARC-145 cells and primary porcine pulmonary alveolar macrophages led to significant reduction of STAT3 protein level. Several strains of both PRRSV type 1 and type 2 led to a similar reduction of STAT3 protein level but had a minimal effect on its transcripts. The PRRSV-mediated STAT3 reduction was in a dose-dependent manner as the STAT3 level decreased, along with incremental amounts of PRRSV inocula. Further study showed that nonstructural protein 5 (nsp5) of PRRSV induced the STAT3 degradation by increasing its polyubiquitination level and shortening its half-life from 24 h to approximately 3.5 h. The C-terminal domain of nsp5 was shown to be required for the STAT3 degradation. Moreover, the STAT3 signaling in the cells transfected with nsp5 plasmid was significantly inhibited. These results indicate that PRRSV antagonizes the STAT3 signaling by accelerating STAT3 degradation via the ubiquitin-proteasomal pathway. This study provides insight into the PRRSV interference with the JAK/STAT3 signaling, leading to perturbation of the host innate and adaptive immune responses. IMPORTANCE: The typical features of immune responses in PRRSV-infected pigs are delayed onset and low levels of virus neutralizing antibodies, as well as weak cell-mediated immunity. Lymphocyte development and differentiation rely on cytokines, many of which signal through the JAK/STAT signaling pathway to exert their biological effects. Here, we discovered that PRRSV antagonizes the JAK/STAT3 signaling by inducing degradation of STAT3, a master transcription activator involved in multiple cellular processes and the host immune responses. The nsp5 protein of PRRSV is responsible for the accelerated STAT3 degradation. The PRRSV-mediated antagonizing STAT3 could lead to suppression of a broad spectrum of cytokines and growth factors to allow virus replication and spread in host animals. This may be one of the reasons for the PRRSV interference with the innate immunity and its poor elicitation of protective immunity. This finding provides insight into PRRSV pathogenesis and its interference with the host immune responses. CI - Copyright (c) 2017 American Society for Microbiology. FAU - Yang, Liping AU - Yang L AD - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA. FAU - Wang, Rong AU - Wang R AD - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA. FAU - Ma, Zexu AU - Ma Z AD - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA. FAU - Xiao, Yueqiang AU - Xiao Y AD - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA. FAU - Nan, Yuchen AU - Nan Y AD - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA. FAU - Wang, Yu AU - Wang Y AD - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA. FAU - Lin, Shaoli AU - Lin S AD - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA. FAU - Zhang, Yan-Jin AU - Zhang YJ AD - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA zhangyj@umd.edu. LA - eng PT - Journal Article DEP - 20170118 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (STAT3 Transcription Factor) RN - 0 (Ubiquitin) RN - 0 (Viral Nonstructural Proteins) RN - 106956-32-5 (Oncostatin M) RN - EC 2.7.10.2 (Janus Kinases) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) SB - IM MH - Animals MH - Cell Line MH - Humans MH - Immunity, Innate MH - Janus Kinases/*metabolism MH - Oncostatin M/pharmacology MH - Porcine Reproductive and Respiratory Syndrome/immunology/*metabolism/*virology MH - Porcine respiratory and reproductive syndrome virus/*physiology MH - Proteasome Endopeptidase Complex/metabolism MH - Protein Binding MH - Protein Interaction Domains and Motifs MH - Proteolysis MH - STAT3 Transcription Factor/*metabolism MH - *Signal Transduction/drug effects MH - Swine MH - Transcription, Genetic MH - Ubiquitin/metabolism MH - Ubiquitination MH - Viral Nonstructural Proteins/chemistry/genetics/*metabolism MH - Virus Replication PMC - PMC5244345 OTO - NOTNLM OT - JAK/STAT signaling OT - PRRSV nsp5 OT - STAT3 OT - innate immunity OT - porcine reproductive and respiratory syndrome virus (PRRSV) OT - signal transducer and activator of transcription 3 EDAT- 2016/11/25 06:00 MHDA- 2017/05/16 06:00 PMCR- 2017/07/18 CRDT- 2016/11/25 06:00 PHST- 2016/10/20 00:00 [received] PHST- 2016/11/21 00:00 [accepted] PHST- 2016/11/25 06:00 [pubmed] PHST- 2017/05/16 06:00 [medline] PHST- 2016/11/25 06:00 [entrez] PHST- 2017/07/18 00:00 [pmc-release] AID - JVI.02087-16 [pii] AID - 02087-16 [pii] AID - 10.1128/JVI.02087-16 [doi] PST - epublish SO - J Virol. 2017 Jan 18;91(3):e02087-16. doi: 10.1128/JVI.02087-16. Print 2017 Feb 1.