| IED ID | IndEnz0002003576 |
| Enzyme Type ID | protease003576 |
| Protein Name |
Interferon regulatory factor 3 IRF-3 |
| Gene Name | IRF3 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MGTPKPRILPWLVSQLDLGQLEGVAWVNKSRTRFRIPWKHGLRQDAQQEDFGIFQAWAEATGAYVPGRDKPDLPTWKRNFRSALNRKEGLRLAEDRSKDPHDPHKIYEFVNSGVGDFSQPDTSPDTNGGGSTSDTQEDILDELLGNMVLAPLPDPGPPSLAVAPEPCPQPLRSPSLDNPTPFPNLGPSENPLKRLLVPGEEWEFEVTAFYRGRQVFQQTISCPEGLRLVGSEVGDRTLPGWPVTLPDPGMSLTDRGVMSYVRHVLSCLGGGLALWRAGQWLWAQRLGHCHTYWAVSEELLPNSGHGPDGEVPKDKEGGVFDLGPFIVDLITFTEGSGRSPRYALWFCVGESWPQDQPWTKRLVMVKVVPTCLRALVEMARVGGASSLENTVDLHISNSHPLSLTSDQYKAYLQDLVEGMDFQGPGES |
| Enzyme Length | 427 |
| Uniprot Accession Number | Q14653 |
| Absorption | |
| Active Site | |
| 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 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 their 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, PubMed:27302953). {ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:27302953, ECO:0000269|PubMed:33440148, 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}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | DNA_BIND 5..111; /note=IRF tryptophan pentad repeat; /evidence=ECO:0000255|PROSITE-ProRule:PRU00840 |
| EC Number | |
| Enzyme 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: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). {ECO:0000269|PubMed:16154084, ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:27302953, ECO:0000269|PubMed:31413131, ECO:0000269|PubMed:32972995, ECO:0000269|PubMed:33440148, ECO:0000303|PubMed:11846977, ECO:0000303|PubMed:16846591, ECO:0000303|PubMed:16979567, ECO:0000303|PubMed:20049431}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Alternative sequence (5); Beta strand (27); Chain (1); Compositional bias (2); Cross-link (3); DNA binding (1); Disulfide bond (1); Helix (12); Modified residue (16); Motif (1); Mutagenesis (21); Natural variant (10); Region (3); Sequence conflict (1); Site (2); Turn (1) |
| Keywords | 3D-structure;Activator;Alternative splicing;Antiviral defense;Cytoplasm;DNA-binding;Disease variant;Disulfide bond;Host-virus interaction;Immunity;Innate immunity;Isopeptide bond;Mitochondrion;Nucleus;Phosphoprotein;Reference proteome;Transcription;Transcription regulation;Ubl conjugation |
| Interact With | Q92793; Q9Y3R0; Q14164; P10914; Itself; P05161; Q9Y5Q3; P67775; P06400; P28749; O14730; O43765; Q9UHD2; P0C6X7 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10805757, ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:31413131, ECO:0000305|PubMed:25636800}. Nucleus {ECO:0000269|PubMed:10805757, ECO:0000269|PubMed:31413131, ECO:0000305|PubMed:25636800}. Mitochondrion {ECO:0000269|PubMed:25609812}. Note=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). {ECO:0000269|PubMed:10805757, ECO:0000269|PubMed:25609812}. |
| Modified Residue | MOD_RES 3; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 14; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 75; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 97; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 123; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:P70671"; MOD_RES 180; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 188; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 237; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 244; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 253; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 385; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:22394562"; MOD_RES 386; /note="Phosphoserine; by TBK1"; /evidence="ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:23746807, ECO:0000269|PubMed:27302953"; MOD_RES 396; /note="Phosphoserine; by IKKE and TBK1"; /evidence="ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:23478265, ECO:0000269|PubMed:27302953"; MOD_RES 398; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 404; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:23746807"; MOD_RES 427; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:23746807" |
| 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). 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). {ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:23478265, ECO:0000269|PubMed:23746807, ECO:0000269|PubMed:25636800}.; 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). {ECO:0000269|PubMed:18641315, ECO:0000269|PubMed:18711448, ECO:0000269|PubMed:21167755}.; 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}. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (18) |
| Cross Reference PDB | 1J2F; 1QWT; 1T2K; 1ZOQ; 2O61; 2O6G; 2PI0; 3A77; 3QU6; 5JEJ; 5JEK; 5JEL; 5JEM; 5JEO; 5JER; 6SIV; 6SJA; 7JFL; |
| Mapped Pubmed ID | 10082512; 11092454; 11244049; 11337497; 11404376; 11724783; 11839743; 11867762; 11884139; 11907205; 11940575; 11972054; 12029096; 12133833; 12354379; 12473110; 12524442; 12582166; 12604599; 12692549; 12829834; 12829839; 14557267; 14703513; 14747533; 14747536; 14769151; 14982987; 15047845; 1508672; 15107417; 15175323; 15210742; 15220448; 15251447; 15303122; 15452220; 15767394; 15841462; 15919920; 15955070; 16009940; 16154077; 16182584; 16199137; 16301520; 16306936; 16362036; 16394098; 16501100; 16513254; 16537515; 16585524; 16699525; 16715065; 16914094; 16914100; 16940530; 16984921; 16988763; 17079482; 17126870; 17142768; 17157040; 17215277; 17251580; 1730654; 17328045; 17393359; 17449641; 17483521; 17526488; 17531282; 17540767; 17560375; 17574024; 17599067; 17608743; 17618271; 17626075; 17641046; 17652396; 17703412; 17761676; 18082865; 18216110; 18252870; 18272195; 18272581; 18309294; 18356163; 18362138; 18362887; 18440553; 18450748; 18539711; 18579584; 18583960; 18635538; 18676680; 18713996; 18781139; 18818105; 18922877; 18927075; 19012493; 19017982; 19028691; 19038458; 19052084; 19124752; 19125153; 19152337; 19153595; 19201840; 19211751; 19213861; 19239434; 19258923; 19307177; 19349300; 19380831; 19426920; 19433799; 19434718; 19445677; 19454348; 19515829; 19553679; 19625176; 19646728; 19692168; 19701189; 19706707; 19710021; 19776740; 19826915; 19854139; 19858727; 19890046; 19893624; 19913121; 19926846; 19955181; 19956647; 20048147; 20048166; 20154210; 20161788; 20170763; 20331378; 20351107; 20360684; 20381110; 20403326; 20416917; 20418377; 20453844; 20454685; 20483755; 20485298; 20501320; 20503287; 20511230; 20532218; 20581830; 20604809; 20609418; 20627800; 20628086; 20631144; 20694008; 20711230; 20826620; 20886096; 20933442; 20980500; 21084487; 21102435; 21120614; 21182093; 21200386; 21225257; 21228327; 21245146; 21281747; 21347389; 21419663; 21468605; 21497908; 21596780; 21632562; 21698224; 21768204; 21782231; 21816816; 21835786; 21859832; 21903422; 21931555; 21935451; 21988832; 22000020; 22027828; 22028379; 2211721; 22127978; 22158869; 22170100; 22208359; 22294846; 22307793; 22388039; 22394560; 22579474; 22593165; 22619329; 22705311; 22745372; 22810585; 22843696; 22906770; 22939624; 23027953; 23077293; 23090018; 23121362; 23122814; 23154183; 23281696; 23303668; 23512614; 23532851; 23542224; 23552418; 23596302; 23633948; 23649622; 23650567; 23755934; 23824799; 23994473; 24049179; 24257594; 24275652; 24275658; 24335286; 24385435; 24531619; 24535579; 24560620; 24722368; 24722640; 24726876; 24752990; 24800889; 24807708; 24807717; 24870145; 24872591; 24879293; 25130328; 25159465; 25232931; 25352594; 25444175; 25481026; 25506707; 25609649; 25712217; 25811886; 25843157; 25891802; 25893288; 25923723; 26058929; 26289783; 26611114; 26646986; 26692175; 26719279; 26811330; 26819312; 27045107; 27094905; 27125670; 27129189; 27129228; 27178468; 27314873; 27342840; 27348780; 27411355; 27454487; 27468646; 27503123; 27530922; 27576490; 27696330; 27791205; 27815826; 28102839; 28150813; 28159912; 28192879; 28336364; 28366813; 28409399; 28435159; 28465426; 28566697; 28589097; 28647346; 28717003; 28774478; 28848048; 28939760; 29084253; 29106945; 29290284; 29361124; 29437975; 29677136; 29800227; 29962372; 30004146; 30297339; 30323286; 30485383; 30699354; 30861602; 30867315; 30871003; 31083335; 31121492; 31138826; 31319869; 31333667; 31340999; 31445188; 31451663; 31686982; 31882361; 32075857; 32130408; 32179480; 32284536; 32314919; 32393626; 32413959; 32476569; 32541772; 32545331; 32634441; 32656094; 32783398; 32826280; 33020188; 33078349; 33205822; 33237620; 33253291; 33300875; 33337935; 33391252; 33419081; 33458618; 33479394; 33594613; 33603735; 33637958; 33767151; 33858962; 33907518; 33913550; 33986734; 34315815; 34509038; 34619149; 6162102; 6548414; 7530745; 8176225; 8483949; 8530158; 9096384; 9143706; 9463386; 9541017; 9660935; 9822609; 9861020; |
| Motif | MOTIF 139..149; /note=Nuclear export signal |
| Gene Encoded By | |
| Mass | 47,219 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |