Viral interferon regulatory factors

Abstract

Upon viral infection, the major defensive strategy employed by the host immune system is the activation of the interferon (IFN)-mediated antiviral pathway, which is overseen by IFN regulatory factors (IRFs). In order to complete their life cycles, viruses must find a way to modulate the host IFN-mediated immune response. Kaposi's sarcoma-associated herpesvirus (KSHV), a human tumor-inducing herpesvirus, has developed a unique mechanism for antagonizing cellular IFN-mediated antiviral activity by incorporating viral homolog of the cellular IRFs, called vIRFs, into its genome. Here, we summarize the novel evasion mechanisms by which KSHV, through its vIRFs, circumvents IFN-mediated innate immune responses and deregulates the cell growth control mechanism.

FIG. 1.

An overview of the inhibition of the type I interferon (IFN) pathway of Kaposi's sarcoma-associated herpesvirus (KSHV). After endocytosis, Toll-like receptor (TLR) 3 responds to the uncoating of endocytosed viral particles in the endosome, resulting in the phosphorylation of TLR3. TLR3 then homodimerizes, binds to CD14, and activates TANK-binding kinase 1 (TBK1/IKKE), leading to the phosphorylation of IFN regulatory factor (IRF)3. IRF3 then homodimerizes and translocates to the nucleus, where it binds to p300/CBP, turning on IFN-β gene expression. TBK1 also phosphorylates IRF7, causing it to homodimerize and translocate to the nucleus, where it binds to the IFN-α promoter. Additionally, IRF7 can heterodimerize with IRF3, upon which the complex translocates to the nucleus to activate the IFN-β promoter. The newly expressed IFN-α and IFN-β genes then bind to the IFN-α receptor in both paracrine and autocrine manners, resulting in the phosphorylation and activation of STAT1 and STAT2, which recruit IRF9 to form the IFN-stimulating gene factor 3 (ISGF3) complex. ISGF3 binds to IFN-stimulated response elements (ISRE) and induces IFN-stimulating genes, such as IRF7. Among the KSHV-encoded vIRF proteins, vIRF3 specifically suppresses IRF7 transcriptional activity, whereas vIRF1 and vIRF2 inhibit the induction of the IFN-β promoter by IRF3.

FIG. 2.

Regulation of p53 function by the viral interferon (IFN) regulatory factors (vIRFs). Activation of the network by stresses, including virus replication and DNA damage, stimulates the phosphorylation and acetylation of p53 to increase the levels of activated p53. The activated p53 then binds to its regulatory region, which activates the expression of several target genes. In turn, this transcriptional activation leads to diverse cellular responses, such as apoptosis, cell cycle arrest, or DNA repair. When p53 is no longer needed, it is ubiquitinated by murine double minute 2 (MDM2) and translocates from the nucleus to be degraded. Furthermore, MDM2 is capable of inducing both the monoubiquitination and polyubiquitination of p53 based on its protein levels in the nucleus. Alternatively, the Kaposi's sarcoma-associated herpesvirus (KSHV) vIRFs inhibit p53 protein levels and/or transcriptional activity in discrepant manners.