Ubiquitin-like protein ISG15 (ISG15)
The protein contains 165 amino acids for an estimated molecular weight of 17888 Da.
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. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. 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 l (updated: June 5, 2019)
Protein identification was indicated in the following studies:
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs1921 |
Biological Process
Defense response to bacterium
Defense response to virus
Integrin-mediated signaling pathway
Interferon-gamma production
Interferon-gamma secretion
Interleukin-10 production
Interleukin-10 secretion
ISG15-protein conjugation
Modification-dependent protein catabolic process
Negative regulation of protein ubiquitination
Negative regulation of type I interferon production
Negative regulation of type I interferon-mediated signaling pathway
Negative regulation of viral genome replication
Positive regulation of bone mineralization
Positive regulation of erythrocyte differentiation
Positive regulation of interferon-gamma production
Positive regulation of interleukin-10 production
Regulation of interferon-gamma production
Response to type I interferon
Response to virus
Translesion synthesis
Type I interferon signaling pathway
Viral process
The reference OMIM entry for this protein is 147571
Ubiquitin-like modifier isg15; isg15
Interferon-induced protein ifi-15k; g1p2
Interferon-induced protein 15; ifi15
DESCRIPTION
ISG15 is a ubiquitin-like protein that becomes conjugated to many cellular proteins upon activation by interferon-alpha (IFNA; 147660) and -beta (IFNB; 147640) (Zhao et al., 2005).GENE FUNCTION
Using EMSA analysis, Meraro et al. (2002) showed that PU.1 (SPI1; 165170) forms heterocomplexes with the immune cell-restricted interferon regulatory factors, IRF4 (601900) and IRF8 (ICSBP1; 601565), leading to the transcriptional activation of the ubiquitin-like ISG15. ISG15 is secreted from monocytes in response to type I IFNs and causes natural killer (NK)-cell proliferation and an augmentation of non-MCH (major histocompatibility complex)-restricted cytotoxicity. ISG15 contains a unique subtype of IFN-stimulated response element (ISRE) that allows the binding of both PU.1 and IRFs and the synergistic activation of the element by the heterocomplex. Zhao et al. (2005) identified 158 proteins that were modified by ISG15 in IFNB-treated HeLa cells, including several IFNA- and IFNB-induced antiviral proteins. Most ISG15 targets were constitutively expressed proteins functionally involved in diverse cellular pathways, including RNA splicing, chromatin remodeling and polymerase II transcription, cytoskeleton organization and regulation, stress responses, and translation. Zhao et al. (2005) concluded that ISG15 conjugation impacts both nuclear and cytoplasmic functions and may have a role in regulating transcription and pre-mRNA splicing during the IFNA/IFNB response. Wong et al. (2006) expressed labeled ISG15 in a lung cell line and identified proteins conjugated by ISG15 after IFNB treatment, including HERC5 (608242). Immunoprecipitation and immunoblot analysis confirmed that HERC5 specifically copurified with ISG15. RT-PCR analysis detected upregulated HERC5 expression after IFNB treatment. Suppression of HERC5 using small interfering RNA showed that HERC5 was required for the ISG15 conjugation system (ISGylation) following IFNB treatment. Overexpression of HERC5 in combination with UBE1L (191325) and UBCH8 (UBE2L6; 603890) allowed ISGylation in the absence of IFNB induction. Mutation analysis showed that cys994 within the HECT domain of HERC5 was essential for HERC5 E3 protein ligase activity in ISGylation. Wong et al. (2006) concluded that HERC5 acts as an ISG15 protein ligase after type I IFN stimulation. Okumura et al. (2006) noted that human immunodeficiency virus (HIV)-1 virions assembled in IFN-treated T cells show low infectivity and accumulate at the plasma membrane, and that IFN-mediated inhibition correlates with ISG15 induction. They showed that ectopic ISG15 mimicked the IFN effect and inhibited release of HIV-1 virions without affecting HIV-1 protein synthesis. The ectopic protein specifically inhibited ubiquitination of the HIV Gag protein, a step critical for assembly and release of virions. Furthermore, ectopic ISG15 inhibited ubiquitination of TSG101 (601387) and disrupted interaction of Gag with TSG101, which is required for viral budding. The effect of ISG15 could be reversed by small interfering RNA, which allowed virus replication to proceed in IFN-treated cells. Okumura et al. (2006) suggested that this mechanism in the innate antiviral response could be a target for anti-HIV-1 intervention. Okumura et al. (2008) investigated the effect of ISG15 on the release of Ebola matrix protein VP40 virus-like particles (VLPs). They found that free ISG15 interacted with NEDD4 (602278) and inhibited bu ... More on the omim web site
July 1, 2020: Protein entry updated
Automatic update: OMIM entry 147571 was added.
June 7, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).