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.
