Functional Involvement of Signal Transducers and Activators of Transcription in the Pathogenesis of Influenza A Virus

Abstract

Signal transducers and activators of transcription (STATs) function both as signal transducers and transcription regulators. STAT proteins are involved in the signaling pathways of cytokines and growth factors; thus, they participate in various life activities and play especially critical roles in antiviral immunity. Convincing evidence suggests that STATs can establish innate immune status through multiple mechanisms, efficiently eliminating pathogens. STAT1 and STAT2 can activate the antiviral status by regulating the interferon (IFN) signal. In turn, suppressor of cytokine signaling-1 (SOCS1) and SOCS3 can modulate the activation of STATs and suppress the excessive antiviral immune response. STAT3 not only regulates the IFN signal, but also transduces Interleukin-6 (IL-6) to stimulate the host antiviral response. The function of STAT4 and STAT5 is related to CD4+ T helper (Th) cells, and the specific mechanism of STAT5 remains to be studied. STAT6 mainly exerts antiviral effects by mediating IL-4 and IL-13 signaling. Here, we reviewed the recent findings regarding the critical roles of STATs in the interactions between the host and viral infection, especially influenza A virus (IAV) infection. We also discuss the molecular mechanisms underlying their functions in antiviral responses.

Keywords: STATs; immune response; influenza A virus; interferon.

Figure 1

Arrangement of chromosomal localization and structure of STAT proteins. (A) The arrangement of IFITM gene clusters in humans, chickens, and mice. Arrows indicate the direction of transcription. Exons are represented as color, and introns are in gray. (B) The structure of STAT proteins. STAT proteins are composed of the following domains: N-terminal domain (ND), the convoluted helical domain (CCD), DNA-binding structural domain (DBD), linker domain (LD), Src homology 2 (SH2) domain, and carboxy-terminal transactivating domain (TAD). The STAT proteins consist of six members: STAT1, which possesses two splicing variants (STAT1a and STAT1b), STAT2 and STAT3, which also include two splicing variants (STAT3a and STAT3b), and STAT4, STAT5α, STAT5β, and STAT6.

Figure 2

Schematic diagram for STATs against influenza A virus (IAV) infection. Host-specific pathogen recognition receptors (PRRs), such as RIG-I, MDA5, TLR3, and TLR7, recognize conserved components of IAV and then transmit signals to corresponding adaptor proteins, such as MAVS, TRIF, and MyD88. These adaptor proteins subsequently activate a series of transcription factors, such as IRF3, IRF7, and NF-κB, triggering the expression of cytokines, including IFNs. The influenza virus fusion peptide of hemagglutinin and M2 protein evokes STING pathways to induce IFNβ-expression. The interaction between cytokines and cytokine receptors (CRs) leads to JAK signal transduction, which activates transcription factor STATs. Activated STATs are transferred into the nucleus to regulate the expression of IFN-stimulated genes (ISGs). The dashed blue line represents the nuclear membrane of the cell.