Q764M6 · IRF3_PIG
- ProteinInterferon regulatory factor 3
- GeneIRF3
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids419 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
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. 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.
Activity regulation
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 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. 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.
Features
Showing features for dna binding, site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
DNA binding | 5-111 | IRF tryptophan pentad repeat | ||||
Sequence: KPRILPWLISQLNQGQLEGVAWLDEGHTRFRIPWKHGLRQDAQQEDFGIFQAWAEASGAYTPGKDKPDLPTWKRNFRSALNRKEALRLAEDHSKDPHDPHKIYEFVT | ||||||
Site | 121-122 | Cleavage; by CASP3 | ||||
Sequence: DT | ||||||
Site | 125-126 | Cleavage; by CASP3 | ||||
Sequence: DL |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | mitochondrion | |
Cellular Component | nucleus | |
Molecular Function | DNA-binding transcription factor activity, RNA polymerase II-specific | |
Molecular Function | RNA polymerase II cis-regulatory region sequence-specific DNA binding | |
Biological Process | cellular response to virus | |
Biological Process | defense response to virus | |
Biological Process | immune system process | |
Biological Process | innate immune response | |
Biological Process | positive regulation of DNA-templated transcription | |
Biological Process | positive regulation of interferon-alpha production | |
Biological Process | positive regulation of interferon-beta production | |
Biological Process | positive regulation of type I interferon production | |
Biological Process | regulation of apoptotic process | |
Biological Process | regulation of transcription by RNA polymerase II | |
Biological Process | TRIF-dependent toll-like receptor signaling pathway |
Keywords
- Molecular function
- Biological process
Names & Taxonomy
Protein names
- Recommended nameInterferon regulatory factor 3
- Short namesIRF-3
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Artiodactyla > Suina > Suidae > Sus
Accessions
- Primary accessionQ764M6
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Note: 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.
Keywords
- Cellular component
PTM/Processing
Features
Showing features for chain, modified residue, cross-link, disulfide bond.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000259485 | 1-419 | Interferon regulatory factor 3 | |||
Sequence: MGTQKPRILPWLISQLNQGQLEGVAWLDEGHTRFRIPWKHGLRQDAQQEDFGIFQAWAEASGAYTPGKDKPDLPTWKRNFRSALNRKEALRLAEDHSKDPHDPHKIYEFVTSGVGDFPEPDTSLDLSGRYSTSDTHEDSLDKLLSGMDLASDAGPQSLTLALEQPPQLSLSPSVDAPASCPNLGVRENPLKQLLANDDEWEFQVTVFYRGCQVFQQTVCSPGGLRLVGSEAEDGTLAGQPVRLPDPAASLTDRGVADYVRRVLSCLGGGLALWRAGQWLWAQRLGHCHVYWAMGEELIPDSGHKPDGEVPKDREGGVFDLGPFIEDLIAFIEGSRRSPRYTLWFCMGQSWPQDEPWVKRLVMVKVVPMCLRALVDMARDGGASSLENTVDLHISNSHPLSLTSDQYKACLRDLVEDMDF | ||||||
Modified residue | 3 | Phosphothreonine | ||||
Sequence: T | ||||||
Modified residue | 14 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 75 | Phosphothreonine | ||||
Sequence: T | ||||||
Modified residue | 97 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 123 | Phosphoserine | ||||
Sequence: S | ||||||
Cross-link | 191 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15) | ||||
Sequence: K | ||||||
Modified residue | 235 | Phosphothreonine | ||||
Sequence: T | ||||||
Modified residue | 251 | Phosphothreonine | ||||
Sequence: T | ||||||
Disulfide bond | 265↔287 | |||||
Sequence: CLGGGLALWRAGQWLWAQRLGHC | ||||||
Cross-link | 358 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15) | ||||
Sequence: K | ||||||
Modified residue | 364 | N6-acetyllysine | ||||
Sequence: K | ||||||
Cross-link | 364 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15) | ||||
Sequence: K | ||||||
Modified residue | 383 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 384 | Diphosphoserine | ||||
Sequence: S | ||||||
Modified residue | 384 | Phosphoserine; by TBK1 | ||||
Sequence: S | ||||||
Modified residue | 394 | Phosphoserine; by IKKE | ||||
Sequence: S | ||||||
Modified residue | 396 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 402 | Phosphothreonine | ||||
Sequence: T |
Post-translational modification
Constitutively phosphorylated on many Ser/Thr residues. Activated following phosphorylation by TBK1 and IKBKE. 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. These kinases then phosphorylate the adapter proteins on the pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1. Phosphorylation at Ser-384 is followed by pyrophosphorylation at the same residue, promoting phosphorylation at Ser-394. Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs.
Pyrophosphorylated by UAP1 following phosphorylation at Ser-384 by TBK1. Pyrophosphorylation promotes subsequent phosphorylation at Ser-394, leading to homodimerization of IRF3.
Acetylation at Lys-364 by KAT8 inhibits recruimtent to promoters and transcription factor activity. Acetylation by KAT8 is promoted by phosphorylation at Ser-394.
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.
(Microbial infection) Phosphorylated by pseudorabies virus protein kinase UL13; leading to decreased IRF3 binding to the IRF3-responsive promoters and downstream ISG expression.
Proteolytically cleaved by apoptotic caspases during apoptosis, leading to its inactivation. Cleavage by CASP3 during virus-induced apoptosis inactivates it, preventing cytokine overproduction.
Keywords
- PTM
Proteomic databases
Interaction
Subunit
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).
Interacts with DDX56 (By similarity).
Interacts with NBR1 (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).
Interacts with DDX56 (By similarity).
Interacts with NBR1 (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 interferes 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.
(Microbial infection) Interacts with African swine fever virus (ASFV) E301R; this interaction inhibits nuclear translocation of IRF3 to the nucleus.
(Microbial infection) Interacts with African swine fever virus (ASFV) minor capsid protein M1249L; this interaction mediates IRF3 degradation.
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q764M6 | CREBBP F1RK46 | 8 | EBI-12512266, EBI-12595681 | |
XENO | Q764M6 | PRO_0000038050 P19712 | 4 | EBI-12512266, EBI-10901281 | |
XENO | Q764M6 | Q68871 | 5 | EBI-12512266, EBI-12522528 |
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 118-137 | Disordered | ||||
Sequence: PEPDTSLDLSGRYSTSDTHE | ||||||
Region | 140-419 | Mediates interaction with ZDHHC11 | ||||
Sequence: LDKLLSGMDLASDAGPQSLTLALEQPPQLSLSPSVDAPASCPNLGVRENPLKQLLANDDEWEFQVTVFYRGCQVFQQTVCSPGGLRLVGSEAEDGTLAGQPVRLPDPAASLTDRGVADYVRRVLSCLGGGLALWRAGQWLWAQRLGHCHVYWAMGEELIPDSGHKPDGEVPKDREGGVFDLGPFIEDLIAFIEGSRRSPRYTLWFCMGQSWPQDEPWVKRLVMVKVVPMCLRALVDMARDGGASSLENTVDLHISNSHPLSLTSDQYKACLRDLVEDMDF | ||||||
Region | 198-358 | Interaction with HERC5 | ||||
Sequence: DEWEFQVTVFYRGCQVFQQTVCSPGGLRLVGSEAEDGTLAGQPVRLPDPAASLTDRGVADYVRRVLSCLGGGLALWRAGQWLWAQRLGHCHVYWAMGEELIPDSGHKPDGEVPKDREGGVFDLGPFIEDLIAFIEGSRRSPRYTLWFCMGQSWPQDEPWVK |
Sequence similarities
Belongs to the IRF family.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length419
- Mass (Da)46,646
- Last updated2004-07-05 v1
- Checksum8B731861BE002284
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AB116563 EMBL· GenBank· DDBJ | BAD06317.1 EMBL· GenBank· DDBJ | mRNA |