SH2-containing protein tyrosine phosphatase 2 (SHP-2) has been shown to inhibit the TRIF-dependent production of proinflammatory cytokines and type I interferon in LPS or poly(I-C)-stimulated mouse peritoneal macrophages. SHP-2 overexpression also inhibited TRIF-induced IFN-luciferase reporter gene expression in human embryonic kidney HEK293 cells. Experiments with truncated SHP-2 or truncated TBK1 mutants revealed that C-terminal domain of SHP-2 associates with N-terminal domain of TBK1 when coexpressed in HEK293 cells. Furthermore, SHP-2 is thought to prevent TBK1-mediated downstream substrate phosphorylation in tyrosine phosphatase activity independent manner by binding to kinase domain of TBK1 [An H et al 2006].
Two members of the interferon regulatory factor (IRF) family IRF-3 and IRF-7 are the major modulators of IFN gene expression. Activation of IRF3 and IRF7, which is mediated by TBK1/IKBKE protein kinases, promotes IFN gene expression and the production of IFN developing an effective antiviral immune response (Hemmi H et al. 2004).
Irf3 deficient mice were found to be more vulnerable to virus infection. Mouse cells defective in IRF3 and IRF7 expression totally fail to induce IFN genes in response to viral infection. It was shown on mice and mouse cells that both IRF3 and IRF7 have non redundant and distinct roles (Sato M et al. 2000). IRF3 is expressed at a basal level in normally growing cells and is a major factor in the early induction phase of IFN-alpha/beta production, while the IRF7 gene expression is induced upon IFNs stimulation and IRF7 is involved in the late induction phase.
TBK1-mediated phosphorylation of the adaptor protein TRIF (TICAM1) leads to IRF3 association with TICAM1 in human HEK293T cells suggesting that TICAM1 (TRIF) recruits IRF3 to the activated TLR3 or TLR4 signaling complex through a phosphorylation-dependent mechanism (Liu S et al. 2015).