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. 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, STING1 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. Monomer. Homodimer; phosphorylation-induced. Interacts (when phosphorylated) with CREBBP. Interacts with MAVS (via phosphorylated pLxIS motif). Interacts with TICAM1 (via phosphorylated pLxIS motif). Interacts with STING1 (via phosphorylated pLxIS motif). Interacts with IKBKE and TBK1. Interacts with TICAM2. Interacts with RBCK1. Interacts with HERC5. Interacts with DDX3X; the interaction allows the phosphorylation and activation of IRF3 by IKBKE. Interacts with TRIM21 and ULK1, in the presence of TRIM21; this interaction leads to IRF3 degradation by autophagy. Interacts with RIOK3; RIOK3 probably mediates the interaction of TBK1 with IRF3. Interacts with ILRUN; the interaction inhibits IRF3 binding to its DNA consensus sequence. Interacts with LYAR; this interaction impairs IRF3 DNA-binding activity. Interacts with TRAF3. Interacts with ZDHHC11; ZDHHC11 recruits IRF3 to STING1 upon DNA virus infection and thereby promotes IRF3 activation (By similarity). Interacts with HSP90AA1; the interaction mediates IRF3 association with TOMM70. Interacts with BCL2; the interaction decreases upon Sendai virus infection. Interacts with BAX; the interaction is direct, increases upon virus infection and mediates the formation of the apoptosis complex TOMM70:HSP90AA1:IRF3:BAX (By similarity). (Microbial infection) Interacts with Porcine epidemic diarrhea virus E protein; this interaction prevents IRF3 translocation to the nucleus and thereby prevents type I interferon production. (Microbial infection) Interacts with African swine fever virus (ASFV) P14.5/E120R; this interaction interfers with the recruitment of IRF3 to TBK1, which in turn suppresses IRF3 phosphorylation, decreasing interferon production via the cGAS/STING pathway. (Microbial infection) Interacts with African swine fever virus (ASFV) MGF360-14L; this interaction mediates degradation of IRF3 through TRIM21 and ubiquitin-meditated proteolysis. Shuttles between cytoplasmic and nuclear compartments, with export being the prevailing effect. When activated, IRF3 interaction with CREBBP prevents its export to the cytoplasm. Recruited to mitochondria via TOMM70:HSP90AA1 upon Sendai virus infection. Constitutively phosphorylated on many Ser/Thr residues. Activated following phosphorylation by TBK1 and IKBKE. Innate adapter protein MAVS, STING1 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 the 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. Ubiquitinated; ubiquitination involves RBCK1 leading to proteasomal degradation. Polyubiquitinated; ubiquitination involves TRIM21 leading to proteasomal degradation. Ubiquitinated by UBE3C, leading to its degradation. ISGylated by HERC5 resulting in sustained IRF3 activation and in the inhibition of IRF3 ubiquitination by disrupting PIN1 binding. The phosphorylation state of IRF3 does not alter ISGylation. Proteolytically cleaved by apoptotic caspases during apoptosis, leading to its inactivation. Cleavage by CASP3 during virus-induced apoptosis inactivates it, preventing cytokine overproduction. Belongs to the IRF family.