Antagonizing cytokine-mediated JAK-STAT signaling by porcine reproductive and respiratory syndrome virus

Abstract

Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is activated by myriad cytokines, which are involved in regulation of cell growth, proliferation, differentiation, apoptosis, angiogenesis, immunity and inflammatory response. Because of its significance in immune response, JAK-STAT pathway is often targeted by pathogens, including porcine reproductive and respiratory syndrome virus (PRRSV). PRRSV causes reproductive failure in sows and respiratory disease in pigs of all ages. A typical feature of the immune response to PRRSV infection in pigs is delayed production and low titer of virus neutralizing antibodies, and weak cell-mediated immune response. One of the possible reasons for the weak protective immune response is that PRRSV interferes with cytokine-mediated JAK-STAT signaling. PRRSV inhibits interferon-activated JAK-STAT signaling by blocking nuclear translocation of STAT1 and STAT2. The mechanism is that PRRSV non-structural protein 1β (nsp1β) induces degradation of karyopherin α1 (KPNA1), a critical adaptor in nucleo-cytoplasmic transport. PRRSV also antagonizes IL6-activated JAK-STAT3 signaling via inducing degradation of STAT3. In this review, we briefly introduce JAK-STAT signaling, summarize the PRRSV interference with it, and provide perspective on the perturbation in the context of PRRSV-elicited immune response.

Keywords: Innate immunity; JAK-STAT signaling; JAKs; PRRSV; STATs.

Fig. 1

PRRSV interference with type I IFN-activated JAK-STAT signaling. A. Canonical signaling. IFN-α/β binds to their receptors IFNAR-1 and IFNAR-2 on the cell membrane and activates the JAK-STAT1/STAT2 pathway. The phosphorylated STAT1 and STAT2 form heterodimer, followed by interaction with IRF9 to form interferon-stimulated gene factor 3 (ISGF3). Karyopherin α1 (KPNA1), an adaptor protein binding ISGF3, is essential to mediate the nuclear import of ISGF3 via interaction with karyopherin β1 (KPNB1). The ISGF3 binds to interferon-stimulated response element (ISRE) in DNA to activate transcription of interferon-stimulated genes (ISGs). “P” besides STATs indicates phosphorylation. PRRSV nsp1β inhibits ISGF3 nuclear translocation via inducing degradation of KPNA1. PRRSV N protein also inhibits ISGF3 nuclear translocation. PRRSV nsp2 reduces ISG15 production and conjugation via its deubiquitination activity. PRRSV induces elevation of miRNA miR-30c to downregulate JAK1 and SOCS1 to inhibit JAKs. PRRSV inhibits PKR during its early infection of pulmonary alveolar macrophages. B. STAT1-independent signaling. Type I IFNs activate alternative JAK-STAT2 signaling without STAT1. The ISGF3-like complex binds to ISRE and interferon-gamma-activated sequence (GAS) to activate alternative sets of ISGs. PRRSV reduces STAT2 protein to inhibit this pathway.

Fig. 2

PRRSV interference with JAK-STAT3 signaling activated by IL-6 family cytokines. IL-6 binds to its receptor IL-6R and gp130, leading to JAK phosphorylation of STAT3, followed by STAT3 homodimer formation. KPNA6 is the adaptor protein to bind to STAT3 and interact with KPNB1 for the nuclear translocation. The STAT3 homodimer binds to STAT3 response element (RE) in DNA to activate transcription of target genes. PRRSV nsp5 induces STAT3 degradation to inhibit JAK-STAT3 signaling.

Fig. 3

PRRSV interferes with STAT6 signaling. A. Canonical JAK-STAT6 signaling. IL-4 and IL-13 bind to receptors, leading to JAK phosphorylation of STAT6, followed by homodimer formation and nuclear translocation to activate target genes. PRRSV reduces STAT6 protein level to inhibit the signaling. B. JAK-independent STAT6 signaling. Viral nucleic acids (dsRNA or dsDNA) activate MAVS and STING on mitochondria and endoplasmic reticulum (ER), respectively, leading to TBK1 (TANK-binding kinase 1) phosphorylation of STAT6, followed by homodimer formation and nuclear translocation to activate alternative target genes, including antiviral chemokines. PRRSV reduces STAT6 protein level to inhibit the signaling.