IRF3 Recombinant Rabbit mAb (S-3916-22)

IRF3 (Interferon Regulatory Factor 3) is a constitutively expressed ~55 kDa transcription factor encoded by the IRF3 gene on chromosome 19, present in the cytoplasm of all tissues. Its N-terminal DNA-binding domain (DBD) contains five characteristic tryptophan repeats, while the C-terminus harbors a transcriptional activation domain tightly auto-inhibited by an intramolecular interaction—in the resting state, residues 380–427 at the C-terminus bind to residues 98–240 at the N-terminus, forming a "closed" conformation that blocks DNA-binding capacity. Upon sensing viral nucleic acids by pattern recognition receptors such as RIG-I/MDA5 or TLR3/4, upstream kinases—primarily TBK1/IKKε (or PKA in certain tissues)—phosphorylate multiple serine/threonine residues within the IRF3 C-terminus (notably the S385/S386 and 396–405 clusters). This phosphorylation triggers a conformational switch, exposing a hydrophobic core and promoting homodimerization. The activated dimers translocate to the nucleus, where they associate with CBP/p300 to form the DRAF1 complex, bind to ISRE elements in target gene promoters, and initiate immediate-early transcription of antiviral and chemotactic genes such as IFN-β and RANTES. This transcriptional activation is precisely restrained by the E3 ligase RAD18, which specifically recognizes DNA-bound, phosphorylated IRF3 dimers and catalyzes K63-linked ubiquitination at Lys193, causing IRF3 to dissociate from the IFNB1 promoter and undergo clearance via the autophagy-lysosome pathway, thereby preventing excessive interferon production and associated autoimmune pathology. More exquisitely, IRF3 exhibits non-transcriptional, dual intracellular functions: on one hand, early during viral infection, it directly binds the pro-apoptotic protein Bax via its BH3-like domain, inducing Bax conformational activation and co-translocation to mitochondria, thereby triggering IFN-independent apoptosis—a mechanism that eliminates viral replication factories and curbs persistent infection. On the other hand, under non-infectious hypoxic stress, cytoplasm-retained IRF3 directly engages HIF-1/2α and impedes their nuclear translocation, thereby suppressing hypoxic signaling and metabolic reprogramming—a discovery that unveiled an evolutionarily conserved, novel function of IRF3 in environmental adaptation beyond antiviral defense. Furthermore, in sterile inflammation such as liver fibrosis, IRF3 is phosphorylated by the Gαs-coupled GPCR-cAMP-PKA axis, driving IL-33 release and mediating hepatic stellate cell activation. This multifunctionality—serving as a transcription factor, apoptosis executor, hypoxia signaling suppressor, and metabolic nexus—positions IRF3 far beyond classical antiviral immunity, establishing it as a central intersection point linking infection, cell death, metabolic adaptation, and tissue fibrosis.