STAT3 roles in viral infection: antiviral or proviral?

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which can be activated by cytokines, growth factor receptors, and nonreceptor-like tyrosine kinase. An activated STAT3 translocates into the nucleus and combines with DNA to regulate the expression of target genes involved in cell proliferation, differentiation, apoptosis and metastasis. Recent studies have shown that STAT3 plays important roles in viral infection and pathogenesis. STAT3 exhibits a proviral function in several viral infections, including those of HBV, HCV, HSV-1, varicella zoster virus, human CMV and measles virus. However, in some circumstances, STAT3 has an antiviral function in other viral infections, such as enterovirus 71, severe acute respiratory syndrome coronavirus and human metapneumovirus. This review summarizes the roles of STAT3 in viral infection and pathogenesis, and briefly discusses the molecular mechanisms involved in these processes.

Keywords: JAK/STAT; STAT3; viral infection.

Figure 1.. Schematic structure of STAT3.

STAT3 has two isoforms, STAT3α and STAT3β. STAT3α protein is composed of ND, CCD, DBD, linker domain, SH2 domain and a C-terminal TAD. However, the transactivation domain is absent in the alternative splicing variant, STAT3β. CCD: Coiled-coil domain; DBD: DNA binding domain; ND: N-terminal domain; TAD: Transcriptional activation domain.

Figure 2.. STAT3 activation and signaling regulation.

In response to some cytokines, growth factors and other triggers, STAT3 is phosphorylated by receptor-associated kinases and then forms homo- or heterodimers. STAT3 dimers then translocate to the nucleus where they act as a transcription activator and mediate the expression of a variety of genes. These genes play important roles in inflammation, oncogenesis, cell survival and angiogenesis. It should be noticeable that some key components for STAT3 signaling are regulated by several phosphatases and suppressors. Please see the detail in the text. Arrows indicated the increase, whereas T-line means the blockage. PIAS: Protein inhibitor of activated STAT; SOCS: Suppressor of cytokine signaling.

Figure 3.. STAT3 signaling pathway modulated by the virus infections.

The viruses mainly modulate STAT3 signaling through the IL-6/IL-6R/gp130/JAKs cascade. STAT3 signaling, sometimes triggered by other cytokines, growth factor and tyrosine kinase, are also modified by several viruses. Furthermore, the downstream components of the IL-6/STAT3 cascade can interact with the Ras/Raf/MEK/MAPKs and PI3K/Akt/mTOR pathways. The details about how the viruses regulate STAT3 signaling can be seen in the main text. Main pathways modified by the viruses are indicated with the bold arrow; the broken line indicates that the effects are mainly mediated by in an indirect way. The HBV- and HCV-induced effects on STAT3 signaling are specifically indicated in the red and orange colors, respectively. ER: Endoplasmic reticulum; Mt: Mitochondria; RABV: Rabies virus; ROS: Reactive oxygen species; RSV: Reproductive and respiratory syndrome virus; SOCS: Suppressor of cytokine signaling; TF: Transcription factor; TMEV: Theiler's murine encephalomyelitis virus.