The Molecular Basis of Viral Inhibition of IRF- and STAT-Dependent Immune Responses

Abstract

The antiviral innate immunity is the first line of host defense against virus infections. In mammalian cells, viral infections initiate the expression of interferons (IFNs) in the host that in turn activate an antiviral defense program to restrict viral replications by induction of IFN stimulated genes (ISGs), which are largely regulated by the IFN-regulatory factor (IRF) family and signal transducer and activator of transcription (STAT) family transcription factors. The mechanisms of action of IRFs and STATs involve several post-translational modifications, complex formation, and nuclear translocation of these transcription factors. However, many viruses, including human immunodeficiency virus (HIV), Zika virus (ZIKV), and herpes simplex virus (HSV), have evolved strategies to evade host defense, including alteration in IRF and STAT post-translational modifications, disturbing the formation and nuclear translocation of the transcription complexes as well as proteolysis/degradation of IRFs and STATs. In this review, we discuss and summarize the molecular mechanisms by which how viral components may target IRFs and STATs to antagonize the establishment of antiviral host defense. The underlying host-viral interactions determine the outcome of viral infection. Gaining mechanistic insight into these processes will be crucial in understanding how viral replication can be more effectively controlled and in developing approaches to improve virus infection outcomes.

Keywords: antiviral response; interferon; interferon-regulatory factor; interferon-stimulated gene; signal transducer and activator of transcription signaling; viral antagonism; viral attenuation.

Figure 1

Interferon (IFN)-regulatory factors (IRFs) involved in cytosolic nucleic acid sensing and endosomal Toll-like receptor (TLR) signaling. During virus infection, retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5) recognize cytosolic double-stranded RNA and recruit the adaptor protein mitochondria antiviral signaling protein (MAVS), which leads to the activation of TANK-binding kinase 1 (TBK1)/IκB kinase-ε (IKKε). Cytosolic double-stranded DNA is detected by cyclic-GMP-AMP (cGAMP) synthase (cGAS) or other receptors (such as DEAD-box helicase 41 (DDX41), gamma-IFN-inducible protein 16 (IFI16), not shown) to induce stimulator of IFN genes (STING)-mediated TBK1 and IKKε activation. Activated TBK1/IKKε then phosphorylate IRF3 and IRF7 that translocate into the nucleus for the induction of IFN-β. The sensing of viral pathogen-associated molecular patterns (PAMPs) by endosomal TLR3 or TLR7/8/9 leads to the phosphorylation and activation of IRF5 and IRF7 through adaptor proteins TIR-domain-containing adapter-inducing IFN (TRIF) or myeloid differentiation primary response 88 (MyD88), respectively, for the expression of type I IFNs.

Figure 2

Interferon (IFN)-dependent IFN stimulated gene (ISG) transcription through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. By binding to the IFN-α receptor (IFNAR) or IFN-λ receptor (IFNLR), type I/III IFNs activate the JAK-STAT pathway leading to the formation of IFN-stimulated gene factor 3 (ISGF3) and gamma-IFN activation factor (GAF) complexes. The ligation between IFN-γ and IFN-γ receptor (IFNGR) also activate the GAF complex. ISGF3 and GAF complexes then translocate into the nucleus mediated by importins and recruit additional coactivators, such as CREB binding protein (CBP)/p300 on the IFN-stimulated response element (ISRE)- or gamma IFN activated sequence (GAS)-containing promoters to stimulate expression of a distinct group of ISGs. Eventually, a set of ISGs are produced and amplify the IFN response. IFN-induced suppressor of cytokine signaling (SOCS) proteins inhibit JAK-STAT signaling by binding to phosphorylated tyrosine residues on either JAK1 or tyrosine kinase 2 (TYK2).