Additionally, varicella zoster virus ORF61 interacts specifically
with activated, phosphorylated IRF3, and uses its RING finger E3 ubiquitin ligase domain to ubiquitinate and degrade IRF3 via the proteasome pathway. HIV immune evasion is complex and cell-type dependent; in T cells, it has previously been shown that viral proteins Vpr and Vif disrupt the IFN response via the degradation of IRF3,[46, 47] whereas in dendritic cells (DCs), IRF3 has recently been found to remain intact, but its activation and nuclear translocation are impeded by Vpr. The HIV protein Vpu also degrades IRF3, by binding and directing it to the lysosome. Instead of interfering with IRF3 activation, NS1 from RSV associates with both IRF3 and its co-activator CBP, impeding Midostaurin datasheet their interaction and impairing promoter binding. Several viral proteins indirectly disrupt IRF3 activation by interfering with the 3-MA supplier kinases TBK1 or IKKε. The papain-like protease domain 2 of NSp3 from mouse hepatitis virus (MHV) A59 has been found to de-ubiquitinate
TBK1, decreasing its kinase activity and stabilizing it in an inactive conformation. Although the mechanisms are currently unclear, the severe fever with thrombocytopenia syndrome virus NSs protein and the HSV-1 γ34.5 protein associate with and inhibit TBK1, while the Tula virus glycoprotein Gn disrupts IFN production at the level of the TBK1 complex. Although they do not impede TBK1, the the NP proteins of several arenaviruses associate with the kinase domain of IKKε, impairing its binding to MAVS and preventing it from phosphorylating IRF3. KSHV also inhibits IKKε signalling by encoding an miRNA known as miR-K12-11, which down-regulates IKKε mRNA translation. Lastly, the C6 protein from vaccinia virus interferes with the activation of IRF3 and IRF7 at the level of TBK1/IKKε, via interaction with the kinase scaffold proteins TANK, Tolmetin NAP1 or SINTBAD. As the exact
contribution of these scaffold proteins to antiviral signalling is unclear, elucidation of C6 activity could provide valuable insight into IFN production. Unlike IRF3, IRF7 is basally expressed at very low to undetectable levels in most cells. IFN-β production by IRF3, NF-κB and ATF2/c-jun induces the expression of IRF7. Like IRF3, IRF7 is phosphorylated by TBK1 and IKKε, causing it to heterodimerize with IRF3 and stimulate full type I IFN expression. KSHV ORF45 impedes the phosphorylation and activation of IRF7 (but not IRF3) by competitive inhibition, as it is phosphorylated by IKKε and TBK1 more efficiently than IRF7. ORF45 may also block IRF7 by associating with its inhibitory domain, stabilizing autoinhibitory intramolecular interactions to keep the protein in a closed, inactive conformation.