Skip to content
2000
Volume 24, Issue 10
  • ISSN: 1871-5273
  • E-ISSN: 1996-3181

Abstract

ISG15 is a 15 kDa ubiquitin-like protein that covalently associates with its target proteins by a sequential enzymatic process known as ISGylation. Research on protein ISGylation has increased in recent years, and some studies have suggested that is involved in neuroprotection and neurodegeneration mechanisms. This review outlines the current state of research on the implications of ISG15/ISGylation in other neuropathies such as malignant tumors, ataxia telangiectasia, ischemia, depression, and neurodegenerative diseases such as Alzheimer’s, Parkinson’s diseases, multiple sclerosis, and amyotrophic lateral sclerosis. Based on the studies reported to date, /ISGylation promotes the progression of brain tumors such as glioblastoma. Moreover, /ISGylation seems to play a dual role in neuropathies, demonstrating a neuroprotective effect when there is acute brain damage, but ISG15/ISGylation is associated with reduced neuroprotection when there is chronic damage, such as in neurodegenerative diseases.

Loading

Article metrics loading...

/content/journals/cnsnddt/10.2174/0118715273378149250322050004
2025-04-14
2025-09-24
Loading full text...

Full text loading...

References

  1. ColcaJ.R. FinckB.N. Metabolic mechanisms connecting Alzheimer’s and Parkinson’s diseases: Potential avenues for novel therapeutic approaches.Front. Mol. Biosci.2022992932810.3389/fmolb.2022.929328 35782864
    [Google Scholar]
  2. DandanaA. Ben KhelifaS. ChahedH. MiledA. FerchichiS. Gaucher disease: Clinical, biological and therapeutic aspects.Pathobiology2016831132310.1159/000440865 26588331
    [Google Scholar]
  3. McColganP. TabriziS.J. Huntington’s disease: A clinical review.Eur. J. Neurol.2018251243410.1111/ene.13413 28817209
    [Google Scholar]
  4. KrahnG. HavercampS. Shining the light on mental health in a population at risk: Cerebral palsy and other developmental disabilities.Ann. Intern. Med.2019171537037110.7326/M19‑1951 31382274
    [Google Scholar]
  5. PaulS. Candelario-JalilE. Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies.Exp. Neurol.202133511351810.1016/j.expneurol.2020.113518 33144066
    [Google Scholar]
  6. Zamudio-ArroyoJ.M. Peña-RangelM.T. Riesgo-EscovarJ.R. Ubiquitination: A dynamic regulatory system in organisms.Zamudio-Arro20121526410.22201/fesz.23958723e.2012.2.64
    [Google Scholar]
  7. HerrmannJ. LermanL.O. LermanA. Ubiquitin and ubiquitin-like proteins in protein regulation.Circ. Res.200710091276129110.1161/01.RES.0000264500.11888.f0 17495234
    [Google Scholar]
  8. ZhangD. ZhangD.E. Interferon-stimulated gene 15 and the protein ISGylation system.J. Interferon Cytokine Res.201131111913010.1089/jir.2010.0110 21190487
    [Google Scholar]
  9. BogunovicD. ByunM. DurfeeL.A. Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency.Science201233761021684168810.1126/science.1224026 22859821
    [Google Scholar]
  10. Tecalco-CruzA.C. Ramírez-JarquínJ.O. Cruz-RamosE. Regulation and action of interferon-stimulated gene 15 in breast cancer cells.Hum. Cell202033495496210.1007/s13577‑020‑00414‑x 32813218
    [Google Scholar]
  11. ZhouM.J. ChenF.Z. ChenH.C. ISG15 inhibits cancer cell growth and promotes apoptosis.Int. J. Mol. Med.201739244645210.3892/ijmm.2016.2845 28035359
    [Google Scholar]
  12. MaoH. WangM. CaoB. ZhouH. ZhangZ. MaoX. Interferon-stimulated gene 15 induces cancer cell death by suppressing the NF-κB signaling pathway.Oncotarget2016743701437015110.18632/oncotarget.12160 27659523
    [Google Scholar]
  13. YeungT.L. TsaiC.C. LeungC.S. ISG15 promotes ERK1 isgylation, CD8+ T cell activation and suppresses ovarian cancer progression.Cancers (Basel)2018101246410.3390/cancers10120464 30469497
    [Google Scholar]
  14. DzimianskiJ.V. ScholteF.E.M. BergeronÉ. PeganS.D. ISG15: It’s complicated.J. Mol. Biol.2019431214203421610.1016/j.jmb.2019.03.013 30890331
    [Google Scholar]
  15. ChairatvitK. WongnoppavichA. ChoonateS. Up-regulation of interferon-stimulated gene15 and its conjugates by tumor necrosis factor-α via type I interferon-dependent and -independent pathways.Mol. Cell. Biochem.20123681-219520110.1007/s11010‑012‑1360‑5 22729740
    [Google Scholar]
  16. MalakhovM.P. KimK.I. MalakhovaO.A. JacobsB.S. BordenE.C. ZhangD.E. High-throughput immunoblotting.J. Biol. Chem.200327819166081661310.1074/jbc.M208435200 12582176
    [Google Scholar]
  17. SwaimC.D. ScottA.F. CanadeoL.A. HuibregtseJ.M. Extracellular ISG15 signals cytokine secretion through the LFA-1 integrin receptor.Mol. Cell2017683581590.e510.1016/j.molcel.2017.10.003 29100055
    [Google Scholar]
  18. D’CunhaJ. RamanujamS. WagnerR.J. WittP.L. KnightE. BordenE.C. In vitro and in vivo secretion of human ISG15, an IFN-induced immunomodulatory cytokine.J. Immunol.1950157941004108 8892645
    [Google Scholar]
  19. KnightE. CordovaB. IFN-induced 15-kDa protein is released from human lymphocytes and monocytes.J. Immunol.1950146722802284 2005397
    [Google Scholar]
  20. Tecalco-CruzA.C. Molecular pathways of interferon-stimulated gene 15: Implications in cancer.Curr. Protein Pept. Sci.2021221192810.2174/1389203721999201208200747 33292152
    [Google Scholar]
  21. MalakhovaO.A. ZhangD.E. ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response.J. Biol. Chem.2008283148783878710.1074/jbc.C800030200 18287095
    [Google Scholar]
  22. DurfeeL.A. LyonN. SeoK. HuibregtseJ.M. The ISG15 conjugation system broadly targets newly synthesized proteins: Implications for the antiviral function of ISG15.Mol. Cell201038572273210.1016/j.molcel.2010.05.002 20542004
    [Google Scholar]
  23. OkumuraF. ZouW. ZhangD.E. ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP.Genes Dev.200721325526010.1101/gad.1521607 17289916
    [Google Scholar]
  24. WongJ.J.Y. PungY.F. SzeN.S.K. ChinK.C. HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets.Proc. Natl. Acad. Sci. USA200610328107351074010.1073/pnas.0600397103 16815975
    [Google Scholar]
  25. ZouW. ZhangD.E. The interferon-inducible ubiquitin-protein isopeptide ligase (E3) EFP also functions as an ISG15 E3 ligase.J. Biol. Chem.200628173989399410.1074/jbc.M510787200 16352599
    [Google Scholar]
  26. BurksJ. ReedR.E. DesaiS.D. ISGylation governs the oncogenic function of Ki-Ras in breast cancer.Oncogene201433679480310.1038/onc.2012.633 23318454
    [Google Scholar]
  27. Cruz-RamosE. Macías-SilvaM. Sandoval-HernándezA. Tecalco-CruzA.C. Non-muscle myosin IIA is post-translationally modified by interferon-stimulated gene 15 in breast cancer cells.Int. J. Biochem. Cell Biol.2019107142610.1016/j.biocel.2018.12.002 30529400
    [Google Scholar]
  28. HuangY.F. BulavinD.V. Oncogene-mediated regulation of p53 ISGylation and functions.Oncotarget20145145808581810.18632/oncotarget.2199 25071020
    [Google Scholar]
  29. ParkJ.H. YangS.W. ParkJ.M. Positive feedback regulation of p53 transactivity by DNA damage-induced ISG15 modification.Nat. Commun.2016711251310.1038/ncomms12513 27545325
    [Google Scholar]
  30. YehY.H. YangY.C. HsiehM.Y. YehY.C. LiT.K. A negative feedback of the HIF-1α pathway via interferon-stimulated gene 15 and ISGylation.Clin. Cancer Res.201319215927593910.1158/1078‑0432.CCR‑13‑0018 24056783
    [Google Scholar]
  31. JeonY.J. ChoiJ.S. LeeJ.Y. ISG15 modification of filamin B negatively regulates the type I interferon‐induced JNK signalling pathway.EMBO Rep.200910437438010.1038/embor.2009.23 19270716
    [Google Scholar]
  32. LeeJ.H. BaeJ.A. LeeJ.H. Glycoprotein 90K, downregulated in advanced colorectal cancer tissues, interacts with CD9/CD82 and suppresses the Wnt/-catenin signal via ISGylation of -catenin.Gut201059790791710.1136/gut.2009.194068 20581239
    [Google Scholar]
  33. ParkS.Y. YoonS. KimH. KimK.K. 90K glycoprotein promotes degradation of mutant β-catenin lacking the isgylation or phosphorylation sites in the N-terminus.Neoplasia2016181061862510.1016/j.neo.2016.08.006 27668402
    [Google Scholar]
  34. ParkY.S. KwonY.J. ChunY.J. CYP1B1 activates Wnt/β-catenin signaling through suppression of herc5-mediated isgylation for protein degradation on β-catenin in hela cells.Toxicol. Res.201733321121810.5487/TR.2017.33.3.211 28744352
    [Google Scholar]
  35. Tecalco-CruzA.C. Velasco-LoydenG. Robles-VillarruelL. Interferon-stimulated gene 15 and ISGylation are upregulated in glioblastoma.Biochem. Biophys. Res. Commun.202262114415010.1016/j.bbrc.2022.07.011 35834923
    [Google Scholar]
  36. KingJ.L. BenhabbourS.R. Glioblastoma multiforme: A look at the past and a glance at the future.Pharmaceutics2021137105310.3390/pharmaceutics13071053 34371744
    [Google Scholar]
  37. WirschingH.G. GalanisE. WellerM. Glioblastoma.Handb. Clin. Neurol.201613438139710.1016/B978‑0‑12‑802997‑8.00023‑2 26948367
    [Google Scholar]
  38. DaiY. YuT. YuC. ISG15 enhances glioma cell stemness by promoting Oct4 protein stability.Environ. Toxicol.20223792133214210.1002/tox.23556 35506701
    [Google Scholar]
  39. LiC. CaiY. ChenY. ABCG2 shields against epilepsy, relieves oxidative stress and apoptosis via inhibiting the ISGylation of STAT1 and mTOR.Redox Biol.20247510326210.1016/j.redox.2024.103262 38981367
    [Google Scholar]
  40. NakkaV.P. LangB.T. LenschowD.J. ZhangD.E. DempseyR.J. VemugantiR. Increased cerebral protein ISGylation after focal ischemia is neuroprotective.J. Cereb. Blood Flow Metab.201131122375238410.1038/jcbfm.2011.103 21847135
    [Google Scholar]
  41. HuY. HongX.Y. YangX.F. Inflammation-dependent ISG15 upregulation mediates MIA-induced dendrite damages and depression by disrupting NEDD4/Rap2A signaling.Biochim. Biophys. Acta Mol. Basis Dis.2019186561477148910.1016/j.bbadis.2019.02.020 30826466
    [Google Scholar]
  42. AlmehmadiM.M. Al-HazmiA. AlomeryA. ShafieA. HalawiM. AlsanieW.F. Interferon-stimulated-gene-15 gene polymorphism as a risk factor in major-depressive-disorder patients.Biosci Res201815439343941
    [Google Scholar]
  43. RobertsB. TheunissenF. MastagliaF.L. AkkariP.A. FlynnL.L. Synucleinopathy in amyotrophic lateral sclerosis: A potential avenue for antisense therapeutics?Int. J. Mol. Sci.20222316936410.3390/ijms23169364 36012622
    [Google Scholar]
  44. MarshallK.L. RajbhandariL. VenkatesanA. MaragakisN.J. FarahM.H. Enhanced axonal regeneration of ALS patient iPSC-derived motor neurons harboring SOD1A4V mutation.Sci. Rep.2023131559710.1038/s41598‑023‑31720‑7 37020097
    [Google Scholar]
  45. WangR.G. KaulM. ZhangD.X. Interferon-stimulated gene 15 as a general marker for acute and chronic neuronal injuries.Sheng Li Xue Bao2012645577583 23090498
    [Google Scholar]
  46. SchwartzenburgJ. JunckerM. ReedR. DesaiS. Increased isgylation in cases of TBI-exposed ALS veterans.J. Neuropathol. Exp. Neurol.201978320921810.1093/jnen/nly129 30657969
    [Google Scholar]
  47. Rothblum-OviattC. WrightJ. Lefton-GreifM.A. McGrath-MorrowS.A. CrawfordT.O. LedermanH.M. Ataxia telangiectasia: A review.Orphanet J. Rare Dis.201611115910.1186/s13023‑016‑0543‑7 27884168
    [Google Scholar]
  48. LavinM.F. BirrellG. ChenP. KozlovS. ScottS. GuevenN. ATM signaling and genomic stability in response to DNA damage.Mutat. Res.20055691-212313210.1016/j.mrfmmm.2004.04.020 15603757
    [Google Scholar]
  49. DesaiSD WoodLM TsaiYC ISG15 as a novel tumor biomarker for drug sensitivity.Mol Cancer Ther2008761430910.1158/1535‑7163.MCT‑07‑234518566215
    [Google Scholar]
  50. LiuL.F. DNA topoisomerase poisons as antitumor drugs.Annu. Rev. Biochem.198958135137510.1146/annurev.bi.58.070189.002031 2549853
    [Google Scholar]
  51. DesaiS.D. ReedR.E. BabuS. LorioE.A. ISG15 deregulates autophagy in genotoxin-treated ataxia telangiectasia cells.J. Biol. Chem.201328842388240210.1074/jbc.M112.403832 23212917
    [Google Scholar]
  52. DesaiS.D. HaasA.L. WoodL.M. Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway.Cancer Res.200666292192810.1158/0008‑5472.CAN‑05‑1123 16424026
    [Google Scholar]
  53. WoodL.M. SankarS. ReedR.E. A novel role for ATM in regulating proteasome-mediated protein degradation through suppression of the ISG15 conjugation pathway.PLoS One201161e1642210.1371/journal.pone.0016422 21298066
    [Google Scholar]
  54. JunckerM. KimC. ReedR. HaasA. SchwartzenburgJ. DesaiS. ISG15 attenuates post-translational modifications of mitofusins and congression of damaged mitochondria in Ataxia Telangiectasia cells.Biochim. Biophys. Acta Mol. Basis Dis.20211867616610210.1016/j.bbadis.2021.166102 33617986
    [Google Scholar]
  55. AmbroseM. GoldstineJ.V. GattiR.A. Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells.Hum. Mol. Genet.200716182154216410.1093/hmg/ddm166 17606465
    [Google Scholar]
  56. LeeJ.Y. NaganoY. TaylorJ.P. LimK.L. YaoT.P. Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy.J. Cell Biol.2010189467167910.1083/jcb.201001039 20457763
    [Google Scholar]
  57. OkatsuK. SaishoK. ShimanukiM. p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria.Genes Cells201015888790010.1111/j.1365‑2443.2010.01426.x 20604804
    [Google Scholar]
  58. Valentin-VegaY.A. MacLeanK.H. Tait-MulderJ. Mitochondrial dysfunction in ataxia-telangiectasia.Blood201211961490150010.1182/blood‑2011‑08‑373639 22144182
    [Google Scholar]
  59. KonchaR.R. RamachandranG. SepuriN.B.V. RamaiahK.V.A. CCCP-induced mitochondrial dysfunction - characterization and analysis of integrated stress response to cellular signaling and homeostasis.FEBS J.2021288195737575410.1111/febs.15868 33837631
    [Google Scholar]
  60. González-AmorM. DoradoB. AndrésV. Emerging roles of interferon-stimulated gene-15 in age-related telomere attrition, the DNA damage response, and cardiovascular disease.Front. Cell Dev. Biol.202311112859410.3389/fcell.2023.1128594 37025175
    [Google Scholar]
  61. ZhangW. SunH.S. WangX. DumontA.S. LiuQ. Cellular senescence, DNA damage, and neuroinflammation in the aging brain.Trends Neurosci.202447646147410.1016/j.tins.2024.04.003 38729785
    [Google Scholar]
  62. LathamA.S. MorenoJ.A. GeerC.E. Biological agents and the aging brain: Glial inflammation and neurotoxic signaling.Front. Aging20234124414910.3389/fragi.2023.1244149 37649972
    [Google Scholar]
  63. HurJ.Y. FrostG.R. WuX. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease.Nature2020586783173574010.1038/s41586‑020‑2681‑2 32879487
    [Google Scholar]
  64. LangR. LiH. LuoX. Expression and mechanisms of interferon-stimulated genes in viral infection of the central nervous system (CNS) and neurological diseases.Front. Immunol.202213100807210.3389/fimmu.2022.1008072 36325336
    [Google Scholar]
  65. MathysH. AdaikkanC. GaoF. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution.Cell Rep.201721236638010.1016/j.celrep.2017.09.039 29020624
    [Google Scholar]
  66. SobueA. KomineO. YamanakaK. Neuroinflammation in Alzheimer’s disease: Microglial signature and their relevance to disease.Inflamm. Regen.20234312610.1186/s41232‑023‑00277‑3 37165437
    [Google Scholar]
  67. EjlerskovP. HultbergJ.G. WangJ. Lack of neuronal IFN-β-IFNAR causes lewy body- and Parkinson’s disease-like dementia.Cell2015163232433910.1016/j.cell.2015.08.069 26451483
    [Google Scholar]
  68. ImE. YooL. HyunM. ShinW.H. ChungK.C. Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase activity of parkin.Open Biol.20166816019310.1098/rsob.160193 27534820
    [Google Scholar]
  69. ClarksonB.D.S. GrundE. DavidK. JohnsonR.K. HoweC.L. ISGylation is induced in neurons by demyelination driving ISG15-dependent microglial activation.J. Neuroinflammation202219125810.1186/s12974‑022‑02618‑4 36261842
    [Google Scholar]
  70. FilipiM. JackS. Interferons in the treatment of multiple sclerosis.Int. J. MS Care202022416517210.7224/1537‑2073.2018‑063 32863784
    [Google Scholar]
  71. JohriA. BealM.F. Mitochondrial dysfunction in neurodegenerative diseases.J. Pharmacol. Exp. Ther.2012342361963010.1124/jpet.112.192138 22700435
    [Google Scholar]
  72. RuzC. AlcantudJ.L. Vives MonteroF. DuranR. Bandres-CigaS. Proteotoxicity and neurodegenerative diseases.Int. J. Mol. Sci.20202116564610.3390/ijms21165646 32781742
    [Google Scholar]
  73. KangJ.A. KimY.J. JeonY.J. The diverse repertoire of ISG15: More intricate than initially thought.Exp. Mol. Med.202254111779179210.1038/s12276‑022‑00872‑3 36319753
    [Google Scholar]
  74. LouZ. WeiJ. RiethmanH. Telomere length regulates ISG15 expression in human cells.Aging (Albany NY)20091760862110.18632/aging.100066 20157543
    [Google Scholar]
/content/journals/cnsnddt/10.2174/0118715273378149250322050004
Loading
/content/journals/cnsnddt/10.2174/0118715273378149250322050004
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test