IRF3

This gene encodes a member of the interferon regulatory transcription factor (IRF) family. The encoded protein is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP. This complex translocates to the nucleus and activates the transcription of interferons alpha and beta, as well as other interferon-induced genes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

Interferon Regulatory Factor 3

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 (PubMed:22394562, PubMed:25636800, PubMed:27302953).
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 (PubMed:11846977, PubMed:16846591, PubMed:16979567, PubMed:20049431, PubMed:32972995).
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 (PubMed:16846591, PubMed:16979567, PubMed:20049431).
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 (PubMed:22394562, PubMed:25636800, PubMed:27302953).
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 (PubMed:16154084, PubMed:27302953, PubMed:33440148).
Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages (PubMed:16846591).
In response to Sendai virus infection, is recruited by TOMM70:HSP90AA1 to mitochondrion and forms an apoptosis complex TOMM70:HSP90AA1:IRF3:BAX inducing apoptosis (PubMed:25609812).
Key transcription factor regulating the IFN response during SARS-CoV-2 infection (PubMed:33440148).

Apoptotic processManual Assertion Based On ExperimentTAS:UniProtKB
Cellular response to DNA damage stimulusManual Assertion Based On ExperimentTAS:UniProtKB
Cellular response to exogenous dsRNAIEA:Ensembl
Cellular response to virusManual Assertion Based On ExperimentIDA:UniProtKB
Defense response to virusISS:UniProtKB
Immune system processManual Assertion Based On ExperimentIBA:GO_Central
Lipopolysaccharide-mediated signaling pathwayIEA:Ensembl
Macrophage apoptotic processManual Assertion Based On ExperimentTAS:UniProtKB
MDA-5 signaling pathwayManual Assertion Based On ExperimentTAS:UniProtKB
Positive regulation of I-kappaB kinase/NF-kappaB signalingIEA:Ensembl
Positive regulation of interferon-alpha productionISS:UniProtKB
Positive regulation of interferon-beta productionISS:UniProtKB
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:ARUK-UCL
Positive regulation of type I interferon productionManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of type I interferon-mediated signaling pathwayIEA:Ensembl
Programmed necrotic cell deathIEA:Ensembl
Regulation of apoptotic processManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of inflammatory responseIEA:Ensembl
Regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIBA:GO_Central
TRIF-dependent toll-like receptor signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Type I interferon signaling pathwayIEA:Ensembl

Cytoplasm; Nucleus; Mitochondrion. Shuttles between cytoplasmic and nuclear compartments, with export being the prevailing effect (PubMed:10805757).
When activated, IRF3 interaction with CREBBP prevents its export to the cytoplasm (PubMed:10805757).
Recruited to mitochondria via TOMM70:HSP90AA1 upon Sendai virus infection (PubMed:25609812).

Encephalopathy, acute, infection-induced, 7, herpes-specific (IIAE7):
A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome.

Constitutively phosphorylated on many Ser/Thr residues (PubMed:22394562, PubMed:23478265, PubMed:23746807).
Activated following phosphorylation by TBK1 and IKBKE (PubMed:23478265, PubMed:23746807, PubMed:25636800).
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 (PubMed:25636800).
These kinases then phosphorylate the adapter proteins on the pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800).
Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs (PubMed:25636800).
Ubiquitinated; ubiquitination involves RBCK1 leading to proteasomal degradation (PubMed:18711448).
Polyubiquitinated; ubiquitination involves TRIM21 leading to proteasomal degradation (PubMed:18641315).
Ubiquitinated by UBE3C, leading to its degradation (PubMed:21167755).
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 (PubMed:30878284).
Cleavage by CASP3 during virus-induced apoptosis inactivates it, preventing cytokine overproduction (PubMed:30878284).
(Microbial infection) ISGylated. ISGylation is cleaved and removed by SARS-COV-2 nsp3 which attenuates type I interferon responses.
(Microbial infection) Phosphorylation and subsequent activation of IRF3 is inhibited by vaccinia virus protein E3.