STAT2 signaling and dengue virus infection

Abstract

Dengue virus (DENV) is an important human pathogen whose byzantine relationship with the immune response is poorly understood. DENV causes dengue fever and dengue hemorrhagic fever/dengue shock syndrome, diseases for which palliative care is the only treatment. DENV immunopathogenesis studies are complicated by the lack of an immunocompetent small-animal model, and this has hindered anti-DENV drug and vaccine development. This review describes strategies that DENV uses to evade the type I interferon response and focuses on how data gained from the study of DENV NS5-mediated STAT2 degradation may be used to create immunocompetent DENV mouse models and design anti-DENV therapeutics.

Keywords: NS5; STAT2; antagonism; dengue virus; host tropism; interferon; mouse model.

Figure 1. The DENV virion and genome. (A) DENV contains a capped plus-strand RNA genome that is surrounded by a shell composed of capsid (C) proteins. The capsid is enveloped by a lipid bilayer embedded with envelope (E) and membrane (M) proteins that mediate virus entry into susceptible cells. (B) The DENV genome functions as an mRNA whose translation yields a polyprotein that is processed by the viral NS2B/3 protease and host proteases to give the structural and nonstructural proteins of the virus.

Figure 2.DENV antagonizes IFNα/β signaling. (A) IFNAR1/2 engagement by IFNα/β leads to the activation of Janus kinase 1 (JAK1) and tyrosine kinase 2 (Tyk2), two tyrosine kinases that are associated with IFNAR1/2. Tyk2 and JAK1 phosphorylate signal transducer and activator of transcription 1 (STAT1) and signal transducer and activator of transcription 2 (STAT2), which interact with interferon regulatory factor 9 (IRF9) to form IFN-stimulated gene factor 3 (ISGF3), which recognizes IFN-stimulated response elements (ISREs). Binding of ISGF3 to ISREs leads to the transcription of IFN-stimulated genes (ISGs). Several ISGs, such as ISG20, viperin and IFITM1–3, encode proteins with anti-DENV activity. NS5 inhibits IFNα/β signaling by targeting STAT2 for degradation while the NS2A, NS4A and NS4B proteins inhibit STAT1 phosphorylation. (B) DENV-mediated STAT2 degradation requires proteolytic cleavage of NS5, which promotes its interaction with UBR4, a 600 kD host protein. The interaction of NS5, STAT2 and UBR4 are required for NS5-mediated, proteasome-dependent STAT2 degradation.