IRF3

Interferon regulatory factor 3 (IRF3) is a constitutively expressed, signal-activated transcription factor of the interferon regulatory factor (IRF) family and the principal transcriptional activator of the type I interferon (IFN-alpha/beta) response to viral infection. It has an N-terminal winged-helix DNA-binding domain bearing the IRF tryptophan pentad repeat, which recognizes GAAA-containing interferon-stimulated response elements (ISRE) and IRF/PRD sites, and a C-terminal IRF-association/regulatory domain that maintains the protein as an autoinhibited cytoplasmic monomer in resting cells. Cytosolic nucleic-acid sensing (RIG-I/MDA5 signaling through MAVS for RNA, cGAS signaling through STING for DNA) and TLR3/TLR4 signaling through TRIF converge on the kinases TBK1 and IKBKE, which phosphorylate a conserved pLxIS motif on the adaptors; phospho-adaptors recruit IRF3 and license its phosphorylation by TBK1 at Ser-385/386/396. Phosphorylation relieves autoinhibition, driving IRF3 homodimerization, nuclear accumulation, sequence-specific DNA binding, and recruitment of the coactivators CBP/p300 to form the DRAF1/enhanceosome complex that activates transcription of IFN-beta, IFN-alpha and interferon-stimulated genes. IRF3 shuttles between cytoplasm and nucleus and is heavily regulated by post-translational modification (phosphorylation, Ser-386 pyrophosphorylation by UAP1, ISGylation, ubiquitination, acetylation, deamidation and caspase cleavage). Beyond transcription, activated IRF3 can be recruited to mitochondria by a TOMM70/HSP90 complex and drive a transcription-independent, BAX-dependent apoptotic program. Loss-of-function of IRF3 predisposes to herpes simplex encephalitis, and IRF3 is a major target of viral immune-evasion proteins.

Disorders

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