靶标信息
Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses . Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters . Acts as a more potent activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA) gene and plays a critical role in both the early and late phases of the IFNA/B gene induction . Found in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, is phosphorylated by IKBKE and TBK1 kinases. This induces a conformational change, leading to its dimerization and nuclear localization and association with CREB binding protein (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I IFN and ISG genes. Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages .
Activity regulationi
In the absence of viral infection, maintained as a monomer in an autoinhibited state . Phosphorylation by TBK1 and IKBKE disrupts this autoinhibition leading to the liberation of the DNA-binding and dimerization activities and its nuclear localization where it can activate type I IFN and ISG genes . Phosphorylation and activation follow the following steps: innate adapter protein MAVS, TMEM173/STING or TICAM1 are first activated by viral RNA, cytosolic DNA and bacterial lipopolysaccharide (LPS), respectively, leading to activation of the kinases TBK1 and IKBKE . These kinases then phosphorylate the adapter proteins on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 . Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs