ISG15 explained

Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ISG15 gene.[1] [2] ISG15 is induced by type I interferon (IFN) and serves many functions, acting both as an extracellular cytokine and an intracellular protein modifier. The precise functions are diverse and vary among species but include potentiation of Interferon gamma (IFN-II) production in lymphocytes, ubiquitin-like conjugation to newly-synthesized proteins and negative regulation of the IFN-I response.[3]

Structure

The ISG15 gene consists of two exons and encodes for a 17 kDa polypeptide. The immature polypeptide is cleaved at its carboxy terminus, generating a mature 15 kDa product that terminates with a LRLRGG motif, as found in ubiquitin. The tertiary structure of ISG15 also resembles ubiquitin, despite only ~30% sequence identity. Specifically, this structure consists of two ubiquitin-like domains connected by a polypeptide ‘hinge.’ Of note, ISG15 shows substantial sequence variation among species, with homology as low as 30% between orthologs.[4]

Function

After induction by type I interferon, ISG15 can be found in three forms, each with unique functions:

Extracellular cytokine

ISG15 is secreted from the cell and can be detected in supernatant or blood plasma.[5] [6] ISG15 binds the LFA-1 integrin receptor on NK- and T-cells to potentiate their production of IFN-II,[7] [8] which is essential for mycobacterial immunity.

Intracellular conjugate: ISGylation

In a ubiquitin-like fashion, ISG15 is covalently linked by its C-terminal LRLRGG motif to lysine residues on newly synthesized proteins. This process, termed ISGylation, is catalyzed by a series of conjugating enzymes. The activating E1 enzyme (UBE1L) charges ISG15 by forming a high-energy thiolester intermediate and transfers it to the UbcH8 E2 enzyme. UbcH8 has been identified as the major E2 for ISGylation, although it also functions in ubiquitination. The E2 protein subsequently transfers the ISG15 to specific E3 ligases (Herc5[9]) and relevant intracellular substrates. Only one deconjugating protease with specificity to ISG15 has been identified to date: USP18 (a member of the USP family) cleaves ISG15-peptide fusions and also removes ISG15 (deISGylation) from native conjugates.[10] The effects of ISGylation are incompletely understood and involve both activation and inhibition of antiviral immunity.

Free intracellular molecule

Unconjugated ISG15 negatively regulates IFN-I signaling by preventing the SKP2-mediated proteasomal degradation of USP18, a direct inhibitor of the IFN-I receptor.[11] Absence of ISG15 leads to persistent IFN-I signaling in human, but not mouse, systems.[12]

Clinical significance

ISG15-deficiency is a very rare genetic disorder caused by mutations of the ISG15 gene. It is inherited with an autosomal recessive pattern and is classified as a primary immunodeficiency or inborn error of immunity. Patients present in childhood with infectious, neurologic or dermatologic features. Basal ganglia calcification is observed in all patients reported to date and represents the underlying autoinflammatory disease of excessive IFN-I activity, known as type I interferonopathy. The basal ganglia calcifications may cause epileptic seizures but often are asymptomatic. The IFN-I inflammation may also manifest early in life as ulcerative skin lesions in the armpit, groin and neck regions.[13] Finally, ISG15-deficiency leads to mendelian susceptibility to mycobacterial disease, although with incomplete penetrance. These infections present as fistulizing lymphadenopathies and respiratory symptoms following BCG vaccination.
In pancreatic ductal adenocarcinoma, tumor-associated macrophages secrete ISG15 enhancing the phenotype of cancer stem cells in the tumor.[14]

History

ISG15 was originally identified in the late 1970s as a 15-kDa protein produced in response to type I interferon, a potent class of antiviral cytokines.[15] Given the molecular weight, it was originally termed ‘a 15-kDa protein’, but later renamed interferon-stimulated-gene-15 when the cassette of interferon-stimulated genes were recognized.[16] [17] In 1987 it was identified that ISG15 cross-reacts with anti-ubiquitin antibodies, and subsequent experiments uncovered the ubiquitin-like conjugation of ISG15 to other cellular proteins, coined ‘ISGylation’.[18] [19] Given its inducibility by IFN-I, studies in the following decades focused on the antiviral activity of ISG15. These studies were carried out predominantly with in vitro systems and mouse models, and ascribed several antiviral functions to ISGylation. During this time, it was also discovered that ISG15 could be detected outside of cells. and in human serum samples. This free form of ISG15 could stimulate IFN-II production in lymphocytes. Finally, ISG15 could also be detected as an un-conjugated intracellular molecule with functions independent of ISGylation.[20]

The discovery of humans deficient in ISG15 elucidated the importance of these functions in human biology. ISG15-deficient patients were first identified by their susceptibly to BCG-strain mycobacteria, owing to the essential function of free ISG15 to potentiate the IFN-gamma / Interleukin-12 axis Surprisingly, despite the IFN-inducible nature of ISG15 and the previously-ascribed antiviral functions in mice, ISG15-deficient patients showed no susceptibility to viral infections. In fact, follow-up studies uncovered enhanced type I IFN signatures, manifesting as basal ganglia calcifications akin to TORCH infection but without an infectious etiology. This persistent, low-level inflammation was later shown to confer enhanced resistance to a wide array of viruses. This phenotype results from a previously-unrecognized function of ISG15 to negatively regulate IFN signaling, which is absent in murine systems. Other higher-order mammals (e.g. pig and dog), however, have achieved this negative regulatory function of ISG15, seemingly by convergent evolution.[21]

Further reading

Notes and References

  1. Blomstrom DC, Fahey D, Kutny R, Korant BD, Knight E . Molecular characterization of the interferon-induced 15-kDa protein. Molecular cloning and nucleotide and amino acid sequence . The Journal of Biological Chemistry . 261 . 19 . 8811–6 . July 1986 . 10.1016/S0021-9258(19)84453-8 . 3087979 . free .
  2. Web site: Entrez Gene: ISG15 ISG15 ubiquitin-like modifier.
  3. Subedi P, Huber K, Sterr C, Dietz A, Strasser L, Kaestle F, Hauck SM, Duchrow L, Aldrian C, Monroy Ordonez EB, Luka B, Thomsen AR, Henke M, Gomolka M, Rossler U, Azimzadeh O, Moertl S, Hornhardt S . Towards unravelling biological mechanisms behind radiation-induced oral mucositis via mass spectrometry-based proteomics . Frontiers in Oncology . 13 . June 2023 . 37384298 . 10.3389/fonc.2023.1180642 . 10298177 . free .
  4. Dzimianski JV, Scholte FE, Bergeron É, Pegan SD . ISG15: It's Complicated . Journal of Molecular Biology . 431 . 21 . 4203–4216 . October 2019 . 30890331 . 10.1016/j.jmb.2019.03.013 . 6746611 .
  5. Knight E, Cordova B . IFN-induced 15-kDa protein is released from human lymphocytes and monocytes . Journal of Immunology . 146 . 7 . 2280–4 . April 1991 . 10.4049/jimmunol.146.7.2280 . 2005397 . free .
  6. D'Cunha J, Knight E, Haas AL, Truitt RL, Borden EC . Immunoregulatory properties of ISG15, an interferon-induced cytokine . Proceedings of the National Academy of Sciences of the United States of America . 93 . 1 . 211–5 . January 1996 . 8552607 . 10.1073/pnas.93.1.211 . 40208 . 1996PNAS...93..211D . free .
  7. Recht M, Borden EC, Knight E . A human 15-kDa IFN-induced protein induces the secretion of IFN-gamma . Journal of Immunology . 147 . 8 . 2617–23 . October 1991 . 10.4049/jimmunol.147.8.2617 . 1717569 . free .
  8. Swaim CD, Scott AF, Canadeo LA, Huibregtse JM . Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor . Molecular Cell . 68 . 3 . 581–590.e5 . November 2017 . 29100055 . 10.1016/j.molcel.2017.10.003 . 5690536 .
  9. Woods MW, Kelly JN, Hattlmann CJ, Tong JG, Xu LS, Coleman MD, Quest GR, Smiley JR, Barr SD . 6 . Human HERC5 restricts an early stage of HIV-1 assembly by a mechanism correlating with the ISGylation of Gag . Retrovirology . 8 . 95 . November 2011 . 22093708 . 3228677 . 10.1186/1742-4690-8-95 . free .
  10. Malakhov MP, Malakhova OA, Kim KI, Ritchie KJ, Zhang DE . UBP43 (USP18) specifically removes ISG15 from conjugated proteins . The Journal of Biological Chemistry . 277 . 12 . 9976–81 . March 2002 . 11788588 . 10.1074/jbc.M109078200 . free .
  11. Zhang X, Bogunovic D, Payelle-Brogard B, Francois-Newton V, Speer SD, Yuan C, Volpi S, Li Z, Sanal O, Mansouri D, Tezcan I, Rice GI, Chen C, Mansouri N, Mahdaviani SA, Itan Y, Boisson B, Okada S, Zeng L, Wang X, Jiang H, Liu W, Han T, Liu D, Ma T, Wang B, Liu M, Liu JY, Wang QK, Yalnizoglu D, Radoshevich L, Uzé G, Gros P, Rozenberg F, Zhang SY, Jouanguy E, Bustamante J, García-Sastre A, Abel L, Lebon P, Notarangelo LD, Crow YJ, Boisson-Dupuis S, Casanova JL, Pellegrini S . 6 . Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation . Nature . 517 . 7532 . 89–93 . January 2015 . 25307056 . 10.1038/nature13801 . 4303590 . 2015Natur.517...89Z .
  12. Speer SD, Li Z, Buta S, Payelle-Brogard B, Qian L, Vigant F, Rubino E, Gardner TJ, Wedeking T, Hermann M, Duehr J, Sanal O, Tezcan I, Mansouri N, Tabarsi P, Mansouri D, Francois-Newton V, Daussy CF, Rodriguez MR, Lenschow DJ, Freiberg AN, Tortorella D, Piehler J, Lee B, García-Sastre A, Pellegrini S, Bogunovic D . 6 . ISG15 deficiency and increased viral resistance in humans but not mice . Nature Communications . 7 . 11496 . May 2016 . 27193971 . 10.1038/ncomms11496 . 4873964 . 2016NatCo...711496S .
  13. Martin-Fernandez M, Bravo García-Morato M, Gruber C, Murias Loza S, Malik MN, Alsohime F, Alakeel A, Valdez R, Buta S, Buda G, Marti MA, Larralde M, Boisson B, Feito Rodriguez M, Qiu X, Chrabieh M, Al Ayed M, Al Muhsen S, Desai JV, Ferre EM, Rosenzweig SD, Amador-Borrero B, Bravo-Gallego LY, Olmer R, Merkert S, Bret M, Sood AK, Al-Rabiaah A, Temsah MH, Halwani R, Hernandez M, Pessler F, Casanova JL, Bustamante J, Lionakis MS, Bogunovic D . 6 . Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions . Cell Reports . 31 . 6 . 107633 . May 2020 . 32402279 . 10.1016/j.celrep.2020.107633 . 7331931 . free .
  14. Sainz B, Martín B, Tatari M, Heeschen C, Guerra S . ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells . Cancer Research . 74 . 24 . 7309–20 . December 2014 . 25368022 . 10.1158/0008-5472.CAN-14-1354 . free .
  15. Farrell PJ, Broeze RJ, Lengyel P . Accumulation of an mRNA and protein in interferon-treated Ehrlich ascites tumour cells . Nature . 279 . 5713 . 523–5 . June 1979 . 571963 . 10.1038/279523a0 . 1979Natur.279..523F . 4317436 .
  16. Kessler DS, Levy DE, Darnell JE . Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes . Proceedings of the National Academy of Sciences of the United States of America . 85 . 22 . 8521–5 . November 1988 . 2460869 . 10.1073/pnas.85.22.8521 . 282490 . 1988PNAS...85.8521K . free .
  17. Reich N, Evans B, Levy D, Fahey D, Knight E, Darnell JE . Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element . Proceedings of the National Academy of Sciences of the United States of America . 84 . 18 . 6394–8 . September 1987 . 3476954 . 10.1073/pnas.84.18.6394 . 299082 . 1987PNAS...84.6394R . free .
  18. Haas AL, Ahrens P, Bright PM, Ankel H . Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin . The Journal of Biological Chemistry . 262 . 23 . 11315–23 . August 1987 . 10.1016/S0021-9258(18)60961-5 . 2440890 . free .
  19. Loeb KR, Haas AL . The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins . The Journal of Biological Chemistry . 267 . 11 . 7806–13 . April 1992 . 10.1016/S0021-9258(18)42585-9 . 1373138 . free .
  20. Werneke SW, Schilte C, Rohatgi A, Monte KJ, Michault A, Arenzana-Seisdedos F, Vanlandingham DL, Higgs S, Fontanet A, Albert ML, Lenschow DJ . 6 . ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation . PLOS Pathogens . 7 . 10 . e1002322 . October 2011 . 22028657 . 10.1371/journal.ppat.1002322 . 3197620 . free .
  21. Qiu X, Taft J, Bogunovic D . Developing Broad-Spectrum Antivirals Using Porcine and Rhesus Macaque Models . The Journal of Infectious Diseases . 221 . 6 . 890–894 . March 2020 . 31637432 . 10.1093/infdis/jiz549 . 7050986 .

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