title: Porcine Reproductive and Respiratory Syndrome Virus Antagonizes JAK/STAT3 Signaling via nsp5, Which Induces STAT3 Degradation.
abstract: 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 ∼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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Yang
authors.affiliation: Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
authors.forename: Zexu
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
authors.forename: Yueqiang
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Nan
authors.affiliation: Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
authors.forename: Shaoli
authors.initials: S
authors.lastname: Lin
authors.affiliation: Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA zhangyj@umd.edu.
authors.forename: Yan-Jin
authors.initials: YJ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D053612:Janus Kinases / Q000378:metabolism*; D053683:Oncostatin M / Q000494:pharmacology; D019318:Porcine Reproductive and Respiratory Syndrome / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D019316:Porcine respiratory and reproductive syndrome virus / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D050796:STAT3 Transcription Factor; D025801:Ubiquitin; D017361:Viral Nonstructural Proteins; D053683:Oncostatin M; D053612:Janus Kinases; D046988:Proteasome Endopeptidase Complex
keywords: JAK/STAT signaling; PRRSV nsp5; STAT3; innate immunity; porcine reproductive and respiratory syndrome virus (PRRSV); signal transducer and activator of transcription 3