Fig 1.
Regulatory circuits of the STAT3 signaling pathway.
STAT3 can be activated by a wide range of ligands binding to cytokine, growth factor, or G-protein-coupled receptors. With the exception of receptor tyrosine kinases, these receptors lack intrinsic kinase activity and thus act by recruiting adaptor kinases (e.g., JAKs, SRC) to propagate downstream signals. As a result, STAT3 is phosphorylated at tyrosine 705 (pY705, pink), forms homodimers or heterodimers, and translocates to the nucleus, where it transcribes regulators of various cellular processes. Additionally, STAT3 can be phosphorylated at serine 727 (pS727, purple) by serine/threonine kinases (e.g., MAPK, mTOR, PKCδ), which enhance STAT3 transcriptional activity in the nucleus or direct STAT3 to mitochondria. Acetylation at lysine 685 (K685, red) by histone acetyltransferases (e.g., CREB binding protein CBP/histone acetyltransferase p300) or methylation at lysine 140 (K140, blue) by histone methyltransferases (e.g., SET9) favor or impair STAT3 transcriptional activity, respectively. Unphosphorylated STAT3 exhibits regulatory functions in the nucleus or can be retained in the cytoplasm, where it associates with microtubules and focal adhesions. The activity of STAT3 is tightly regulated by phosphatases (e.g., PTPRD), SOCS3, PIAS3, and miRNAs that fine-tune the temporal pattern of STAT3 activity and its other pathway components. All miRNAs are degrading the mRNAs of the indicated proteins. A, acetylation; CBP, CREB-binding protein; CT-1R, cardiotrophin 1 receptor; CNTFR, ciliary neurotrophic factor receptor; DUSP2, dual specificity protein phosphatase 2; EGFR, epidermal growth factor receptor; GHR, growth hormone receptor; G-CSFR, granulocyte colony-stimulating factor receptor; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; gp130, glycoprotein 130; IFNAR, interferon alpha receptor; IFNGR, interferon gamma receptor; IL, interleukin; JAK, Janus kinase; K140, lysine 140; K685, lysine 685; LIFR, leukemia inhibitory factor receptor; MAPK, mitogen-activated protein kinase; M, methylation; miRNA, microRNA; mTOR, mechanistic target of rapamycin; OSMR, oncostatin-M-specific receptor; P, phosphorylation; p300, histone acetyltransferase p300; PDGFR, platelet-derived growth factor receptor; PIAS3, protein inhibitor of activated STAT protein 3; PKCδ, protein kinase C delta type; pS727, phospho-serine 727; PTPRC, receptor-type tyrosine-protein phosphatase C; PTPRD, receptor-type tyrosine-protein phosphatase D; PTPRT, receptor-type tyrosine-protein phosphatase T; pY705, phospho-tyrosine 705; SET9, histone-lysine N-methyltransferase SET9; SOCS3, suppressor of cytokine signaling 3; SRC, proto-oncogene tyrosine-protein kinase; STAT3, signal transducer and activator of transcription 3; TpoR, thrombopoietin receptor; TRIM28, tripartite motif-containing protein 28.
Fig 2.
Viral manipulation of the STAT3 signaling pathway.
(A) 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) 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.
Table 1.
Virus/STAT3 interactions: Summary of observations and employed methods.
Fig 3.
Viral replicative advantages and pathological consequences related to STAT3-altered function.
(A) Virus-induced perturbation of STAT3 as regulator of apoptosis. In the context of viral infections, apoptosis can be restrained via STAT3, since it favors the expression of antiapoptotic factors (e.g., PCBP2 and BIRC5) or prevents proapoptotic ones (e.g., RTA, FOS, JUN, and NR4A2). In contrast, inhibition of STAT3 by viruses such as IAV and MuV has been associated with the induction of the apoptotic process. (B) Viral manipulation of STAT3 and its effect on immune responses. Viral inhibition of STAT3 can induce a decrease of ISG and APR gene expression and favor immune evasion, as in the case of KSHV and HEV. Virus-mediated STAT3 activation can also have immunosuppressive actions such as impairing DC function (KSHV and HCMV) and favoring the expansion of MDSCs (HCV). In other cases, the proinflammatory actions of STAT3 have been associated with the development of host pathologies such as cancer (KSHV). (C) Virus-induced alteration of STAT3 and its impact on cell and tissue organization. STAT3 activation during HCV infection has been associated with alterations of the MT network. This represents a potential advantage for HCV by favoring virus trafficking along MTs. At the tissue and organ level, STAT3 activation has been associated with the development of fibrosis (HCV), the disruption of endothelial vascular junctions (IAV), and enhanced cell invasion, which favors cancer development (EBV). ANGPTL4, angiopoietin-like protein 4; APR, acute phase response; BIRC5, baculoviral IAP repeat-containing protein 5; CCL5, C-C motif chemokine ligand 5; DCs, dendritic cells; DC-SIGN, dendritic cell-specific ICAM-3-grabbing non-integrin 1; EBV, Epstein–Barr virus; FOS, proto-oncogene c-Fos; HCC, hepatocellular carcinoma; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HEV, hepatitis E virus; HSCs, hepatic stellate cells; IAV, influenza A virus; IDO1, indoleamine 2,3-dioxygenase 1; IL-10, interleukin 10; ISG, interferon-stimulated gene; JUN, proto-oncogene c-Jun; KSHV, Kaposi’s sarcoma-associated herpesvirus; MCL1, induced myeloid leukemia cell differentiation protein Mcl-1; MDSCs, myeloid-derived suppressor cells; MT, microtubule; MUC1, mucin 1 cell surface associated; MuV, mumps virus; NPC, nasopharyngeal carcinoma; NR4A2, nuclear receptor subfamily 4 group A member 2; PCBP2, poly(rC)-binding protein 2; PD-L1, programmed cell death 1 ligand 1; RTA, R transactivator; RVFV, Rift Valley fever virus; STAT3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor beta; Treg, regulatory CD4+ T cell; VZV, varicella-zoster virus.
Table 2.
STAT3 signaling inhibitors, their mechanisms and in vitro antiviral applications.