ISG15

The protein encoded by this gene is a ubiquitin-like protein that is conjugated to intracellular target proteins upon activation by interferon-alpha and interferon-beta. Several functions have been ascribed to the encoded protein, including chemotactic activity towards neutrophils, direction of ligated target proteins to intermediate filaments, cell-to-cell signaling, and antiviral activity during viral infections. While conjugates of this protein have been found to be noncovalently attached to intermediate filaments, this protein is sometimes secreted. [provided by RefSeq, Dec 2012]

ISG15 Ubiquitin-Like Modifier

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).

Defense response to bacteriumManual Assertion Based On ExperimentIMP:UniProtKB
Defense response to virusManual Assertion Based On ExperimentIDA:UniProtKB
Integrin-mediated signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
ISG15-protein conjugationManual Assertion Based On ExperimentIDA:UniProtKB
Modification-dependent protein catabolic processManual Assertion Based On ExperimentIBA:GO_Central
Negative regulation of protein ubiquitinationManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of type I interferon-mediated signaling pathwayManual Assertion Based On ExperimentIMP:ARUK-UCL
Negative regulation of viral genome replicationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of bone mineralizationISS:UniProtKB
Positive regulation of erythrocyte differentiationIEA:Ensembl
Positive regulation of interferon-beta productionManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of interferon-gamma productionManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of interleukin-10 productionManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of protein oligomerizationManual Assertion Based On ExperimentIDA:UniProtKB
Protein localization to mitochondrionManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of interferon-gamma productionManual Assertion Based On ExperimentIMP:UniProtKB
Response to type I interferonManual Assertion Based On ExperimentIDA:UniProtKB
Response to virusManual Assertion Based On ExperimentIDA:UniProtKB

Cytoplasm; Secreted. Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins.

Immunodeficiency 38, with basal ganglia calcification (IMD38):
A primary immunodeficiency predisposing individuals to severe clinical disease upon infection with weakly virulent mycobacteria, including Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccines. Patients are also susceptible to Salmonella and Mycobacterium tuberculosis infections. Affected individuals have intracranial calcification.

S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins.
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.