| IED ID | IndEnz0002016210 |
| Enzyme Type ID | protease016210 |
| Protein Name |
Ubiquitin-like protein ISG15 Interferon-induced 15 kDa protein Interferon-induced 17 kDa protein IP17 Ubiquitin cross-reactive protein hUCRP |
| Gene Name | ISG15 G1P2 UCRP |
| 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 | MGWDLTVKMLAGNEFQVSLSSSMSVSELKAQITQKIGVHAFQQRLAVHPSGVALQDRVPLASQGLGPGSTVLLVVDKCDEPLSILVRNNKGRSSTYEVRLTQTVAHLKQQVSGLEGVQDDLFWLTFEGKPLEDQLPLGEYGLKPLSTVFMNLRLRGGGTEPGGRS |
| Enzyme Length | 165 |
| Uniprot Accession Number | P05161 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | FUNCTION: Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein (PubMed:33727702). Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Isgylation of the viral sensor IFIH1/MDA5 promotes IFIH1/MDA5 oligomerization and triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses (PubMed:33727702). Can also isgylate: EIF2AK2/PKR which results in its activation, DDX58/RIG-I which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. The secreted form acts through the integrin ITGAL/ITGB2 receptor to initiate activation of SRC family tyrosine kinases including LYN, HCK and FGR which leads to secretion of IFNG and IL10; the interaction is mediated by ITGAL (PubMed:29100055). {ECO:0000269|PubMed:1373138, ECO:0000269|PubMed:16009940, ECO:0000269|PubMed:16112642, ECO:0000269|PubMed:16428300, ECO:0000269|PubMed:16434471, ECO:0000269|PubMed:16872604, ECO:0000269|PubMed:18305167, ECO:0000269|PubMed:19270716, ECO:0000269|PubMed:19357168, ECO:0000269|PubMed:2005397, ECO:0000269|PubMed:20133869, ECO:0000269|PubMed:20308324, ECO:0000269|PubMed:20639253, ECO:0000269|PubMed:21543490, ECO:0000269|PubMed:22693631, ECO:0000269|PubMed:22859821, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:29100055, ECO:0000269|PubMed:33727702, ECO:0000269|PubMed:7526157, ECO:0000269|PubMed:8550581}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Beta strand (10); Chain (1); Cross-link (1); Disulfide bond (1); Domain (2); Helix (6); Initiator methionine (1); Modified residue (1); Motif (1); Mutagenesis (7); Natural variant (1); Propeptide (1); Region (1); Sequence conflict (1); Site (1) |
| Keywords | 3D-structure;Antiviral defense;Cytoplasm;Direct protein sequencing;Disulfide bond;Host-virus interaction;Immunity;Innate immunity;Isopeptide bond;Reference proteome;Repeat;S-nitrosylation;Secreted;Ubl conjugation pathway |
| Interact With | O75369; Q9BYX4; Q14653; O75688; O60260-5; P41226; Q9UMW8; P0C6U8; Q6TQR6; P03495; P03502; K0BWD0; K9N7C7; P0C6X7; P0DTD1 |
| Induction | INDUCTION: Strongly induced upon exposure to type I interferons, viruses, LPS, and other stresses, including certain genotoxic stresses. {ECO:0000269|PubMed:22859821}. |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22859821}. Secreted {ECO:0000269|PubMed:22859821}. Note=Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins. |
| Modified Residue | MOD_RES 78; /note=S-nitrosocysteine; alternate; /evidence=ECO:0000269|PubMed:18606809 |
| Post Translational Modification | PTM: S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins. {ECO:0000269|PubMed:18606809}.; PTM: Induced as an inactive, precursor protein that is cleaved by specific proteases to expose the C-terminal diglycine (LRLRGG) motif. This motif is essential not only for its conjugation to substrates but also for its recognition by the relevant processing proteases. {ECO:0000269|PubMed:2477469, ECO:0000269|PubMed:3350799}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (1); X-ray crystallography (14) |
| Cross Reference PDB | 1Z2M; 2HJ8; 3PHX; 3PSE; 3R66; 3RT3; 3SDL; 5TL6; 5W8T; 5W8U; 6BI8; 6FFA; 6XA9; 7RBS; 7S6P; |
| Mapped Pubmed ID | 11092454; 11095724; 11112487; 11337497; 11404376; 12029096; 12055236; 12067988; 12525615; 12582176; 14769151; 14976209; 15047845; 15208624; 15485925; 15670748; 15684817; 15702989; 16122702; 16139798; 16189514; 16352599; 16407192; 16424026; 16641915; 16699525; 16715065; 16775314; 16815975; 16884686; 16914094; 17069755; 17097911; 17222803; 17289916; 1730654; 17353931; 17376915; 17653289; 17692280; 18057259; 18287095; 18566215; 18583345; 18591409; 18597038; 18627608; 18953482; 19043203; 19073728; 19074853; 19125153; 19378789; 19430494; 19656964; 19846672; 19913121; 19956859; 19959962; 20035788; 20093371; 20124702; 20157543; 20164219; 20219937; 20385878; 20542004; 20628086; 20628624; 21245344; 21266548; 21399617; 21544738; 21757684; 21808041; 22093708; 22100648; 2211721; 22185919; 22706304; 22729740; 22740306; 23121362; 23212917; 23318454; 23588721; 23750257; 24024201; 24056783; 24237697; 24300530; 24386835; 24452380; 24768535; 24844324; 25165091; 25307056; 25368022; 25416956; 25429107; 25609649; 25749047; 25905045; 25906440; 26036210; 26226047; 26259872; 26361997; 26560068; 26563749; 26617815; 26763998; 26833585; 26844778; 26872785; 26919245; 27193971; 27534820; 27545325; 27626177; 27659523; 27926780; 28186990; 28202760; 28204879; 28287327; 28438633; 28467275; 28543875; 28630501; 28724761; 28881486; 28931677; 29367604; 29463763; 29518394; 29555370; 29580840; 29626479; 29853735; 30213559; 30411299; 30485383; 30529400; 30765861; 30771383; 30858391; 31428903; 31444947; 31455647; 31501523; 31765674; 32020185; 32127658; 32402279; 32416603; 32423918; 32472071; 32513696; 32553163; 32597933; 32641707; 32686110; 32738280; 32845033; 32931521; 33024031; 33073304; 33203188; 33214684; 33292152; 33533212; 33797839; 34110168; 34556814; 34599178; 34661519; 34784198; 6162102; 6548414; 7559393; 9096384; 9525617; 9861020; |
| Motif | MOTIF 152..157; /note=LRLRGG |
| Gene Encoded By | |
| Mass | 17,888 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |