IRF3
entrez
3661
canonical
uniprot
Q14653
canonical
ensembl
ENSG00000126456
resolver
ensp
ENSP00000366344
resolver
ensp
ENSP00000470069
resolver
ensp
ENSP00000470512
resolver
ensp
ENSP00000471358
resolver
ensp
ENSP00000471402
resolver
ensp
ENSP00000471896
resolver
ensp
ENSP00000472582
resolver
ensp
ENSP00000472601
resolver
ensp
ENSP00000472700
resolver
ensp
ENSP00000560806
resolver
ensp
ENSP00000560810
resolver
ensp
ENSP00000702297
resolver
ensp
ENSP00000740923
resolver
enst
ENST00000593922
resolver
enst
ENST00000598808
resolver
enst
ENST00000599144
resolver
enst
ENST00000601373
resolver
genesymbol
IRF3
resolver
hgnc
HGNC:6118
resolver
uniprot
A8K7L2
resolver
uniprot
B2RAZ3
resolver
uniprot
E2GIM5
resolver
uniprot
E2GIM6
resolver
uniprot
E2GIM7
resolver
uniprot
E2GIM8
resolver
uniprot
E2GIM9
resolver
uniprot
M0QYT9
resolver
uniprot
M0R0R8
resolver
uniprot
Q5FBY1
resolver
uniprot
Q5FBY2
resolver
uniprot
Q5FBY4
resolver
uniprot
Q7Z5G6
resolver
uniprot
Q96GL3
resolver
uniprot_entry
E2GIM5_HUMAN
resolver
uniprot_entry
E2GIM6_HUMAN
resolver
uniprot_entry
E2GIM7_HUMAN
resolver
uniprot_entry
E2GIM8_HUMAN
resolver
uniprot_entry
E2GIM9_HUMAN
resolver
uniprot_entry
IRF3_HUMAN
resolver
uniprot_entry
M0QYT9_HUMAN
resolver
uniprot_entry
Q96GL3_HUMAN
resolver
uniprot_sec
A8K7L2
resolver
uniprot_sec
B2RAZ3
resolver
uniprot_sec
M0R0R8
resolver
uniprot_sec
Q5FBY1
resolver
uniprot_sec
Q5FBY2
resolver
uniprot_sec
Q5FBY4
resolver
uniprot_sec
Q7Z5G6
resolver
activity_regulation
ACTIVITY REGULATION: In the absence of viral infection, maintained as a monomer in an autoinhibited state (PubMed:16846591, PubMed:16979567, PubMed:20049431). 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 (PubMed:25636800). Phosphorylation and activation follow the following steps: innate adapter proteins, such as 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, PubMed:36603579). These kinases then phosphorylate the adapter proteins on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800, PubMed:36603579). Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs (PubMed:25636800, PubMed:27302953). {ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:27302953, ECO:0000269|PubMed:33440148, ECO:0000269|PubMed:36603579, ECO:0000303|PubMed:16846591, ECO:0000303|PubMed:16979567, ECO:0000303|PubMed:20049431}.; ACTIVITY REGULATION: (Microbial infection) Activated upon coronavirus SARS-CoV-2 infection. {ECO:0000269|PubMed:33440148}.
uniprot
proteins
amino_acid_sequence
MGTPKPRILPWLVSQLDLGQLEGVAWVNKSRTRFRIPWKHGLRQDAQQEDFGIFQAWAEATGAYVPGRDKPDLPTWKRNFRSALNRKEGLRLAEDRSKDPHDPHKIYEFVNSGVGDFSQPDTSPDTNGGGSTSDTQEDILDELLGNMVLAPLPDPGPPSLAVAPEPCPQPLRSPSLDNPTPFPNLGPSENPLKRLLVPGEEWEFEVTAFYRGRQVFQQTISCPEGLRLVGSEVGDRTLPGWPVTLPDPGMSLTDRGVMSYVRHVLSCLGGGLALWRAGQWLWAQRLGHCHTYWAVSEELLPNSGHGPDGEVPKDKEGGVFDLGPFIVDLITFTEGSGRSPRYALWFCVGESWPQDQPWTKRLVMVKVVPTCLRALVEMARVGGASSLENTVDLHISNSHPLSLTSDQYKAYLQDLVEGMDFQGPGES
uniprot
proteins
disease_involvement
DISEASE: Encephalopathy, acute, infection-induced, 7, herpes-specific (IIAE7) [MIM:616532]: 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. {ECO:0000269|PubMed:26216125, ECO:0000269|PubMed:40973797}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
uniprot
proteins
function
FUNCTION: 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:24049179, PubMed:25636800, PubMed:27302953, PubMed:31340999, PubMed:36603579, PubMed:8524823, PubMed:39362857). 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, PubMed:36603579, PubMed:8524823). 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, PubMed:36603579). 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, PubMed:36603579). 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, PubMed:36603579). 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). {ECO:0000269|PubMed:16154084, ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:24049179, ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:27302953, ECO:0000269|PubMed:31340999, ECO:0000269|PubMed:31413131, ECO:0000269|PubMed:32972995, ECO:0000269|PubMed:33440148, ECO:0000269|PubMed:36603579, ECO:0000269|PubMed:39362857, ECO:0000269|PubMed:8524823, ECO:0000303|PubMed:11846977, ECO:0000303|PubMed:16846591, ECO:0000303|PubMed:16979567, ECO:0000303|PubMed:20049431}.
uniprot
proteins
mass_dalton
47219
uniprot
proteins
mutagenesis
MUTAGEN 77..78; /note="KR->NG: Abolishes nuclear localization."; /evidence="ECO:0000269|PubMed:10805757"; MUTAGEN 86..87; /note="RK->LQ: No effect on subcellular localization."; /evidence="ECO:0000269|PubMed:10805757"; MUTAGEN 116; /note="D->A: Does not affect cleavage by CASP3."; /evidence="ECO:0000269|PubMed:30878284"; MUTAGEN 121..125; /note="DTSPD->ATSPA: Abolished cleavage by CASP3."; /evidence="ECO:0000269|PubMed:30878284"; MUTAGEN 139..140; /note="IL->MM: Abolishes nuclear export."; /evidence="ECO:0000269|PubMed:10805757"; MUTAGEN 193; /note="K->R: Highly diminished ISGylation; when associated with R-360 and R-366."; /evidence="ECO:0000269|PubMed:20308324"; MUTAGEN 285; /note="R->S: Abolished interaction with STING1, MAVS or TICAM1."; /evidence="ECO:0000269|PubMed:27302953"; MUTAGEN 288; /note="H->S: Decreased interaction with TICAM1."; /evidence="ECO:0000269|PubMed:27302953"; MUTAGEN 290; /note="H->S: Decreased interaction with TICAM1."; /evidence="ECO:0000269|PubMed:27302953"; MUTAGEN 313; /note="K->S: Abolished interaction with STING1, MAVS or TICAM1."; /evidence="ECO:0000269|PubMed:27302953"; MUTAGEN 360; /note="K->R: Highly diminished ISGylation; when associated with R-193 and R-366."; /evidence="ECO:0000269|PubMed:20308324"; MUTAGEN 366; /note="K->R: Highly diminished ISGylation; when associated with R-193 and R-360."; /evidence="ECO:0000269|PubMed:20308324"; MUTAGEN 385..386; /note="SS->AA: Complete loss of viral infection induced phosphorylation."; /evidence="ECO:0000269|PubMed:9566918"; MUTAGEN 385; /note="S->A,D,E: Complete loss of viral infection induced phosphorylation."; /evidence="ECO:0000269|PubMed:10920266, ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:25636800"; MUTAGEN 385; /note="S->A: Abolishes PBLD-induced IFNB, ISG15 and IFITM3 expression during virus infection; when associated with A-386."; /evidence="ECO:0000269|PubMed:39362857"; MUTAGEN 386; /note="S->A: Complete loss of viral infection induced phosphorylation. Abolished pyrophosphorylation. Abolishes PBLD-induced IFNB, ISG15 and IFITM3 expression after virus infection; when associated with A-385."; /evidence="ECO:0000269|PubMed:10920266, ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:23746807, ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:36603579, ECO:0000269|PubMed:39362857"; MUTAGEN 386; /note="S->E: Phosphomimetic mutant; interacts with CREBBP; when associated with E-396."; /evidence="ECO:0000269|PubMed:27302953"; MUTAGEN 390; /note="T->A: Does not affect pyrophosphorylation."; /evidence="ECO:0000269|PubMed:36603579"; MUTAGEN 396..405; /note="SNSHPLSLTS->ANAHPLALAA: Complete loss of viral infection induced phosphorylation."; /evidence="ECO:0000269|PubMed:9566918"; MUTAGEN 396..405; /note="SNSHPLSLTS->DNDHPLDLDD: Acts as a constitutively activated IRF3."; /evidence="ECO:0000269|PubMed:9566918"; MUTAGEN 396..398; /note="SNS->ANA: Complete loss of viral infection induced phosphorylation."; MUTAGEN 396; /note="S->A: Impaired ability to activate STING1-dependent NF-kappa-B signaling."; /evidence="ECO:0000269|PubMed:40973797"; MUTAGEN 396; /note="S->E: Phosphomimetic mutant; interacts with CREBBP; when associated with E-386."; /evidence="ECO:0000269|PubMed:27302953"; MUTAGEN 402..405; /note="SLTS->ALAA: Complete loss of viral infection induced phosphorylation.
uniprot
proteins
post_translational_modification
PTM: 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, PubMed:36603579). Innate adapter proteins, such as 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). Phosphorylation at Ser-386 is followed by pyrophosphorylation at the same residue, promoting phosphorylation at Ser-396 (PubMed:36603579). Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs (PubMed:25636800, PubMed:36603579). Phosphorylation of IRF3 at Ser-385 and Ser-386 plays an important role in the PBLD-triggered IFN-I cascade (PubMed:39362857). {ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:23478265, ECO:0000269|PubMed:23746807, ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:36603579, ECO:0000269|PubMed:39362857}.; PTM: Pyrophosphorylated by UAP1 following phosphorylation at Ser-386 by TBK1 (PubMed:36603579). Pyrophosphorylation promotes subsequent phosphorylation at Ser-396, leading to homodimerization of IRF3 (PubMed:36603579). {ECO:0000269|PubMed:36603579}.; PTM: Acetylation at Lys-366 by KAT8 inhibits recruitment to promoters and transcription factor activity. Acetylation by KAT8 is promoted by phosphorylation at Ser-396. {ECO:0000250|UniProtKB:P70671}.; PTM: Deamidation of Asn-85 by CTPS1 prevents IRF3 from binding DNA, thereby inhibiting the transcription factor activity. {ECO:0000250|UniProtKB:P70671}.; PTM: 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). Deubiquitinated by USP5 on both 'Lys-48'-linked unanchored and 'Lys-63'-linked anchored polyubiquitin, leading to inhibition of anti-RNA viral innate immunity (PubMed:39761299). {ECO:0000269|PubMed:18641315, ECO:0000269|PubMed:18711448, ECO:0000269|PubMed:21167755, ECO:0000269|PubMed:39761299}.; PTM: 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. {ECO:0000269|PubMed:18641315, ECO:0000269|PubMed:18711448, ECO:0000269|PubMed:20308324}.; PTM: 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). {ECO:0000269|PubMed:30878284}.; PTM: (Microbial infection) ISGylated. ISGylation is cleaved and removed by SARS-COV-2 nsp3 which attenuates type I interferon responses. {ECO:0000269|PubMed:32726803}.; PTM: (Microbial infection) Phosphorylation and subsequent activation of IRF3 is inhibited by vaccinia virus protein E3. {ECO:0000269|PubMed:11124948}.; PTM: (Microbial infection) Phosphorylated by herpes simplex virus 1/HHV-1 US3 at Ser-175 to prevent IRF3 activation. {ECO:0000269|PubMed:24049179}.
uniprot
proteins
protein_family
IRF family
uniprot
proteins
pubmed
10805757
uniprot
proteins
pubmed
10920266
uniprot
proteins
pubmed
11035028
uniprot
proteins
pubmed
11124948
uniprot
proteins
pubmed
11314014
uniprot
proteins
pubmed
11846977
uniprot
proteins
pubmed
12186937
uniprot
proteins
pubmed
12471095
uniprot
proteins
pubmed
12702806
uniprot
proteins
pubmed
14517278
uniprot
proteins
pubmed
14555995
uniprot
proteins
pubmed
14555996
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
14739303
uniprot
proteins
pubmed
15057824
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15510218
uniprot
proteins
pubmed
16153868
uniprot
proteins
pubmed
16154084
uniprot
proteins
pubmed
16281057
uniprot
proteins
pubmed
16846591
uniprot
proteins
pubmed
16979567
uniprot
proteins
pubmed
18641315
uniprot
proteins
pubmed
18711448
uniprot
proteins
pubmed
19153231
uniprot
proteins
pubmed
19557502
uniprot
proteins
pubmed
20049431
uniprot
proteins
pubmed
20308324
uniprot
proteins
pubmed
20628368
uniprot
proteins
pubmed
21167755
uniprot
proteins
pubmed
22394562
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23478265
uniprot
proteins
pubmed
23746807
uniprot
proteins
pubmed
24049179
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
25609812
uniprot
proteins
pubmed
25636800
uniprot
proteins
pubmed
26216125
uniprot
proteins
pubmed
26347139
uniprot
proteins
pubmed
27302953
uniprot
proteins
pubmed
27980081
uniprot
proteins
pubmed
28331227
uniprot
proteins
pubmed
29427864
uniprot
proteins
pubmed
29802199
uniprot
proteins
pubmed
30863402
uniprot
proteins
pubmed
30867312
uniprot
proteins
pubmed
30878284
uniprot
proteins
pubmed
31340999
uniprot
proteins
pubmed
31413131
uniprot
proteins
pubmed
32726803
uniprot
proteins
pubmed
32972995
uniprot
proteins
pubmed
33440148
uniprot
proteins
pubmed
35914352
uniprot
proteins
pubmed
35922005
uniprot
proteins
pubmed
36603579
uniprot
proteins
pubmed
39362857
uniprot
proteins
pubmed
39761299
uniprot
proteins
pubmed
40973797
uniprot
proteins
pubmed
41747053
uniprot
proteins
pubmed
8524823
uniprot
proteins
pubmed
9566918
uniprot
proteins
pubmed
9803267
uniprot
proteins
sequence_length
427
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10805757, ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:31340999, ECO:0000269|PubMed:31413131, ECO:0000269|PubMed:35922005, ECO:0000269|PubMed:36603579, ECO:0000269|PubMed:39761299, ECO:0000305|PubMed:25636800}. Nucleus {ECO:0000269|PubMed:10805757, ECO:0000269|PubMed:31340999, ECO:0000269|PubMed:31413131, ECO:0000269|PubMed:35922005, ECO:0000269|PubMed:36603579, ECO:0000269|PubMed:39761299, ECO:0000305|PubMed:25636800}. Mitochondrion {ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:39362857}. Note=Shuttles between cytoplasmic and nuclear compartments, with export being the prevailing effect (PubMed:10805757, PubMed:35922005). 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). {ECO:0000269|PubMed:10805757, ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:35922005}.
uniprot
proteins