Viral manipulation of the STAT3 signaling pathway.

<p><b>(A)</b> Viruses activating STAT3 function and the mechanisms involved. Viral proteins such as HBx, NS5A, core, NSs, EBNA2, LMP1, US28, and IE1 induce STAT3 activation either directly or by favoring the action of upstream positive regulators. Viruses like HCMV and KSHV code for homologues of human interleukins such as IL-10 and IL-6. Alternatively, virus-induced activation of STAT3 can be achieved by the inhibition of negative regulators such as SOCS3, PTPRD, TRIM28, and Let-7a. In the case of some viruses, STAT3 activation (VZV and ZIKV) or STAT3-mediated effects (IAV) have been described, but the mechanisms involved have not been fully elucidated. All miRNAs are degrading the mRNAs of the indicated proteins. <b>(B)</b> Viruses suppressing STAT3 function and the mechanisms involved. Virus-mediated inactivation of STAT3 can be attained by decreasing its phosphorylation (KSHV, IAV, and hMPV), inducing STAT3 protein degradation (MuV), hampering its transcriptional activity (MeV), or altering its subcellular localization (HCMV, RABV, HEV, and hMPV). EBNA2, Epstein–Barr virus nuclear antigen 2; EBV, Epstein–Barr virus; HBV, hepatitis B virus; HBx, hepatitis B virus X protein; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HEV, hepatitis E virus; hMPV, human metapneumovirus; IAV, influenza A virus; IE1, intermediate-early protein 1; IL-6, interleukin 6; IL-10, interleukin 10; IRAK1, interleukin 1 receptor-associated kinase 1; JAK1, Janus kinase 1; KSHV, Kaposi’s sarcoma-associated herpesvirus; LMP1, latent membrane protein 1; miRNA, microRNA; MeV, measles virus; MK2, mitogen-activated protein kinase 2; MuV, mumps virus; NS5A, non-structural protein 5A; NSs, non-structural proteins; P, phosphorylation; PKCδ, protein kinase C delta type; PTPRD, receptor-type tyrosine-protein phosphatase D; RABV, rabies virus; ROS, reactive oxygen species; RVFV, Rift Valley fever virus; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; TRIM28, tripartite motif-containing protein 28; u-STAT3, unphosphorylated STAT3; vIL-10, viral IL-10; vIL-6, viral IL-6; VZV, varicella-zoster virus; ZIKV, Zika virus.