Affinage

ISG15

Ubiquitin-like protein ISG15 · UniProt P05161

Length
165 aa
Mass
17.9 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ISG15 is an interferon-induced ubiquitin-like protein that operates through three functionally separable modes—covalent ISGylation of intracellular substrates, free intracellular ISG15, and secreted extracellular ISG15—to coordinate antiviral immunity, cellular metabolism, genome stability, and intercellular signaling (PMID:22859821, PMID:33571167, PMID:32472071). As a covalent modifier, ISG15 is conjugated to substrates via a dedicated E1 (Uba7/UBE1L)–E2 (UBE2L6/UbcH8) cascade whose structural basis for ISG15-specific activation and E1-to-E2 thioester transfer has been resolved by cryo-EM (PMID:37553340, PMID:38042859), after maturation of pro-ISG15 to its active C-terminal diglycine form by a thiol protease (PMID:10455185). ISGylation tunes diverse pathways: it modifies STING at K289 to drive oligomerization and type I IFN induction (PMID:37864791), modifies replication-fork proteins to stabilize stalled forks and protect nascent DNA, including in BRCA1/2-deficient cells (PMID:36216822, PMID:37783689), and reshapes metabolism by ISGylating glycolytic enzymes such as HK2 and PFK1 to suppress glycolysis while sustaining mitochondrial respiration and mitophagy (PMID:33571167, PMID:32472071, PMID:38309955, PMID:35842904). ISGylation also controls protein stability and quality control, targeting misfolded p53 to the 20S proteasome (PMID:24844324, PMID:31455647) and modifying substrates including PTEN, KPNA2, filamin-C, and MFN1/2 to alter their turnover and downstream behavior (PMID:27980214, PMID:37115698, PMID:37501099, PMID:39465252). Free intracellular ISG15 instead acts non-covalently: it stabilizes the deISGylase USP18 to negatively feedback on type I IFN signaling and to restrict flaviviruses by preventing NS5-mediated STAT2 degradation (PMID:27193971, PMID:38384473), and it engages STAT2 to promote ISGF3 assembly and ISRE-driven transcription (PMID:36315588). Secreted ISG15 functions as a cytokine, binding the αI domain of the LFA-1 integrin to activate SRC-family kinases and drive IFN-γ and IL-10 secretion from lymphocytes, a pathway essential for human antimycobacterial immunity (PMID:29100055, PMID:22859821, PMID:32553163). DeISGylation is carried out principally by USP18, whose ISG15-specific protease activity is structurally defined (PMID:28881486), with USP16 acting as a cross-reactive deISGylase (PMID:38055744). Human ISG15 deficiency causes chronically elevated IFN signaling and mycobacterial susceptibility without broad viral susceptibility, distinguishing the secreted/free functions from intracellular ISGylation (PMID:27193971, PMID:22859821).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1999 High

    Established how ISG15 becomes a competent conjugation tag, showing that the precursor must be proteolytically matured to expose the reactive C-terminal glycine.

    Evidence Biochemical purification of a 100-kDa thiol protease and in vitro processing assay mapping Gly157-Gly158 cleavage in human fibroblast extracts

    PMID:10455185

    Open questions at the time
    • Identity of the physiological processing protease in vivo not pinned to a single gene
    • Does not address conjugation machinery
  2. 2006 Medium

    Linked ISGylation to crosstalk with the ubiquitin-proteasome system, indicating ISG15 conjugation can antagonize polyubiquitination.

    Evidence siRNA knockdown of ISG15 and its E2 UbcH8 in tumor cells with western blot of polyubiquitinated proteins

    PMID:16424026

    Open questions at the time
    • Specific substrates not identified
    • Mechanism of antagonism not resolved
  3. 2007 Medium

    Showed ISGylation participates in innate immune signaling regulation by influencing RIG-I modification in competition with a ubiquitin E3 ligase.

    Evidence Co-IP and ectopic expression of UbcH8/ISG15/RNF125 with RIG-I ubiquitination and ISGylation assays

    PMID:17719635

    Open questions at the time
    • Overexpression-based; physiological relevance of competition unclear
    • No endogenous validation
  4. 2012 High

    Defined the secreted, extracellular function of ISG15 as essential for human antimycobacterial immunity, separable from intracellular ISGylation.

    Evidence Human ISG15-deficient patients with leukocyte secretion and NK-cell IFN-γ assays

    PMID:22859821

    Open questions at the time
    • Receptor for secreted ISG15 not yet identified in this study
    • Secretion mechanism unknown
  5. 2014 Medium

    Identified misfolded p53 as an ISGylation substrate routed for 20S proteasomal degradation, implicating ISGylation in protein quality control.

    Evidence Co-IP, in vitro 20S degradation assay, site-directed mutagenesis, and Isg15 knockout mouse cells

    PMID:24844324

    Open questions at the time
    • E3 ligase directing p53 ISGylation not defined
    • Single lab
  6. 2016 High

    Resolved the dual nature of the free-ISG15/USP18 axis by showing free ISG15 stabilizes USP18 to dampen type I IFN signaling in humans.

    Evidence ISG15-deficient patient fibroblasts complemented with WT vs. conjugation-deficient ISG15ΔGG, USP18 protein and IFN readouts

    PMID:27193971

    Open questions at the time
    • Human-specific; murine difference unexplained mechanistically
    • Structural basis of ISG15-USP18 stabilization not in this study
  7. 2020 Medium

    Dissected the regulation of ISG15 secretion, showing intracellular ISGylation restrains secretion while viral effectors modulate it, and that secreted ISG15 signals through LFA-1.

    Evidence ISG15 secretion assays with conjugation mutants and viral effector (influenza B NS1, SARS-CoV-2 PLpro) expression across cell types

    PMID:32553163

    Open questions at the time
    • Molecular route of unconventional ISG15 secretion not defined
    • Single lab
  8. 2017 High

    Mapped extracellular ISG15 signaling to a defined receptor and kinase cascade, establishing LFA-1/SFK as the conduit for cytokine induction.

    Evidence Direct in vitro binding to the CD11a αI domain, CD11a-/- splenocytes, LFA-1 and SFK inhibitor studies, ISG15 mutagenesis, NK-92 IFN-γ release

    PMID:29100055

    Open questions at the time
    • Downstream transcriptional program beyond IFN-γ/IL-10 not fully mapped
    • How LFA-1 engagement is tuned in vivo unclear
  9. 2023 High

    Provided the structural basis for ISG15-specific activation, explaining how Uba7 and UBE2L6 achieve selectivity distinct from ubiquitin.

    Evidence Cryo-EM structures of Uba7-UBE2L6-ISG15 adenylate/thioester intermediates with structure-guided mutagenesis

    PMID:37553340 PMID:38042859

    Open questions at the time
    • E3 (HERC5) substrate-selection step not structurally resolved here
    • Full conjugation handoff to substrate not visualized
  10. 2023 High

    Explained viral subversion of ISG15 by structurally defining how PLpro distinguishes ISG15's two UBL domains from K48 di-ubiquitin.

    Evidence Crystallography, cryo-EM, NMR, cross-linking MS, and affinity measurements of SARS-CoV-2 PLpro with ISG15

    PMID:37185902

    Open questions at the time
    • In-cell consequences of differential UBL engagement not quantified
    • Generalization to other viral deISGylases unaddressed
  11. 2017 Medium

    Defined USP18 as the highly ISG15-specific protease and revealed its receptor-binding, catalysis-independent role in shutting off IFN signaling.

    Evidence Crystal structures of USP18 and USP18-ISG15 complex with biochemical cleavage assays

    PMID:28881486

    Open questions at the time
    • Review-level structural summary
    • In vivo deISGylation substrate scope not addressed
  12. 2024 Medium

    Identified USP16 as a cross-reactive deISGylase, broadening the enzyme set that removes ISG15 from metabolic substrates.

    Evidence ISG15 activity-based profiling, recombinant USP16 in vitro cleavage, USP16 depletion, and substrate identification

    PMID:38055744

    Open questions at the time
    • Physiological importance relative to USP18 unclear
    • Substrate selectivity rules undefined
  13. 2021 High

    Established ISGylation as a metabolic rheostat, showing IRF3-driven ISG15 ISGylates glycolytic enzymes to limit lactate and thermogenesis.

    Evidence Isg15 KO mice phenocopying adipocyte IRF3 KO, lactate rescue, and ISGylation assays of glycolytic enzymes

    PMID:33571167

    Open questions at the time
    • Which specific glycolytic enzyme ISGylation events are causal not fully delineated
    • Tissue specificity of effect not mapped
  14. 2024 Medium

    Pinpointed HK2 and PFK1 as ISGylation substrates whose modification suppresses glycolysis to preserve cardiac mitochondrial capacity during infection.

    Evidence MS ISGylome, enzymatic activity assays, structural modeling, Seahorse flux in cardiomyocytes and ISG15 KO mouse heart

    PMID:38309955

    Open questions at the time
    • ISGylation site stoichiometry in vivo unknown
    • E3 directing these modifications not identified
  15. 2020 High

    Linked ISGylation to mitochondrial quality control by showing it is required for mitophagy, OXPHOS, and stem-cell self-renewal in pancreatic cancer.

    Evidence CRISPR ISG15 KO with WT vs. conjugation-deficient complementation, OXPHOS/mitophagy assays, and in vivo tumor formation

    PMID:32472071

    Open questions at the time
    • Mitochondrial ISGylation substrates not enumerated
    • Connection to mitophagy machinery not mechanistically resolved
  16. 2022 Medium

    Generalized the requirement of ISGylation for mitochondrial respiration to human patient-derived macrophages.

    Evidence iPSC-derived macrophages from ISG15-deficient patients with WT vs. conjugation-deficient complementation and respiration assays

    PMID:35842904

    Open questions at the time
    • Respiratory-chain substrates of ISGylation undefined
    • Partial rescue by free ISG15 unexplained
  17. 2022 Medium

    Connected ISGylation to genome maintenance, showing it modifies replication-fork proteins downstream of cGAS-STING to mitigate replication stress.

    Evidence Mre11 inactivation, ISG15 KO cells, iPOND, fork-stability and aphidicolin-sensitivity assays

    PMID:36216822

    Open questions at the time
    • Specific fork substrates of ISGylation not fully identified
    • Single lab
  18. 2023 Medium

    Extended the fork-protection role to a therapeutic context, showing IFNβ restores fork stability in BRCA1/2-deficient cells strictly via ISG15/ISGylation.

    Evidence ISG15 siRNA/KO, IFNβ treatment, DNA fiber assays in BRCA1/2-deficient cells, ISGylation complementation

    PMID:37783689

    Open questions at the time
    • Substrate(s) of fork-protective ISGylation undefined
    • Clinical translation untested
  19. 2023 Medium

    Defined ISGylation of STING at K289 as a switch for STING oligomerization and IFN induction in DNA sensing.

    Evidence ISG15 KO cells, site-directed mutagenesis of STING lysines, oligomerization and IFN induction assays, molecular modeling

    PMID:37864791

    Open questions at the time
    • E3 directing STING ISGylation not identified
    • Single lab
  20. 2022 Medium

    Identified a free-ISG15 role in IFN signal amplification through direct STAT2 interaction and ISGF3 assembly.

    Evidence ISG15 KO cells/mice, conjugation inhibition, ISG15-STAT2 Co-IP, ISGF3 and ISRE reporter assays

    PMID:36315588

    Open questions at the time
    • Structural basis of ISG15-STAT2 binding unknown
    • Relation to USP18-mediated negative feedback unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct E3 ligases and deISGylases select among the hundreds of ISGylation substrates to achieve pathway-specific outcomes remains unresolved.
  • No systematic substrate-to-E3 mapping in the corpus
  • Site-level and stoichiometric rules for substrate ISGylation undefined
  • Mechanism integrating free vs. conjugated vs. secreted ISG15 in vivo unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0031386 protein tag activity 8 GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3 GO:0005739 mitochondrion 3 GO:0005829 cytosol 3
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-73894 DNA Repair 2
Partners
HERC5ITGALPARP12STAT2UBA7UBE2L6USP18

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 Extracellular ISG15 signals through the LFA-1 integrin receptor (CD11a/CD18; αLβ2 integrin) to promote IFN-γ and IL-10 secretion. ISG15 bound directly to the αI domain of CD11a in vitro; LFA-1 inhibition or CD11a knockout blocked cytokine secretion. ISG15 engagement of LFA-1 led to activation of SRC family kinases (SFKs), and SFK inhibition blocked cytokine secretion. NK-92 cell IFN-γ release assay, direct in vitro binding to αI domain, CD11a-/- mouse splenocytes, LFA-1 inhibitor studies, SFK inhibitor studies, site-directed mutagenesis of ISG15 signaling residues Molecular cell High 29100055
1999 Pro-ISG15 is synthesized as a precursor that requires processing by a constitutive 100-kDa thiol protease to expose the mature C-terminal glycine (Gly157-Gly158 cleavage). The processing enzyme is stimulated 12-fold by micromolar ubiquitin and is related to yeast Ubp1. Biochemical purification from human lung fibroblast extracts, in vitro processing assay, thiol protease inhibitor studies, pH rate analysis, tryptic peptide sequencing The Journal of biological chemistry High 10455185
2010 Free intracellular ISG15 stabilizes USP18 protein by protecting it from proteasomal degradation, and this stabilization of USP18 is the mechanism by which ISG15 downregulates type I IFN-α/β signaling in humans (but not in mice). ISG15-deficient human cells display chronically elevated ISG signaling as a result of reduced USP18 levels. ISG15-deficient patient fibroblasts, complementation with WT ISG15 vs. ISG15ΔGG (conjugation-deficient), USP18 protein level measurement, IFN signaling readouts Nature communications High 27193971
2012 Secreted ISG15 from granulocytes/leukocytes stimulates IFN-γ production by lymphocytes (including NK cells) in response to mycobacterial infection; this extracellular signaling function is essential for antimycobacterial immunity in humans. Loss of intracellular ISGylation did not confer susceptibility to viral infections in these patients. Human ISG15-deficient patients (inherited loss-of-function mutations), leukocyte secretion assays, NK cell IFN-γ production assays Science (New York, N.Y.) High 22859821
2023 Cryo-EM structures of human Uba7 (UBE1L) in complex with UBE2L6 and ISG15 adenylate or ISG15 thioester intermediate revealed the molecular basis for ISG15 activation and E1-to-E2 thioester transfer. The structures demonstrate unique overall architecture compared to the ubiquitin conjugation pathway and explain Uba7's exquisite specificity for ISG15 and UBE2L6. Cryo-EM structure determination, biochemical assays, human cell-based functional validation, mutagenesis of specificity determinants Nature communications High 37553340
2023 Cryo-EM and crystal structures of SARS-CoV-2 PLpro complexed with human ISG15 and K48-linked di-ubiquitin revealed that the two UBL domains of ISG15 are differentially engaged by PLpro compared to K48-Ub2, and differential binding stabilities of the two UBL/Ub domains explain PLpro substrate selectivity. Crystal structures, cryo-EM, solution NMR, cross-linking mass spectrometry, binding affinity measurements Nature communications High 37185902
2023 A 3.45 Å cryo-EM structure of the UBE1L (Uba7)-UBE2L6 complex bound to activated ISG15 reveals the molecular basis of ISG15 recognition and UBE2L6 recruitment, and identifies the ISG15 C-terminal ubiquitin-like domain as critical for the adenylation reaction. Mutants with altered selectivity for ISG15 vs. ubiquitin conjugation pathways were designed based on the structure. Cryo-EM structure, biochemical characterization using viral effector proteins (SARS-CoV-2 PLpro, influenza B NS1), mutagenesis of ISG15 and UBE2L6 Nature communications High 38042859
2006 Elevated ISG15 in tumor cells antagonizes the ubiquitin/26S proteasome pathway by interfering with protein polyubiquitination. siRNA knockdown of ISG15 increased polyubiquitinated protein levels; siRNA knockdown of the E2 enzyme UbcH8 (blocking ISG15 conjugate formation) also increased polyubiquitinated proteins. siRNA knockdown of ISG15 and UbcH8 in tumor cell lines, western blot analysis of polyubiquitinated proteins Cancer research Medium 16424026
2014 ISG15 (Isg15) covalently modifies p53 at two sites (N- and C-terminal) via ISGylation. ISGylated p53 is degraded by the 20S proteasome. ISGylation preferentially targets misfolded, dominant-negative p53. Isg15 deletion in normal cells suppresses p53 activity. Co-immunoprecipitation, ISGylation assays, 20S proteasome degradation assay, Isg15 knockout mouse cells, site-directed mutagenesis Cell cycle (Georgetown, Tex.) Medium 24844324
2019 USP18 isopeptidase activity promotes accumulation of misfolded p53 by removing ISG15 from p53; ISG15 is required for degradation of misfolded dominant-negative p53. Depletion of ISG15 causes accumulation of misfolded dominant-negative p53 and enhances HIV-1 replication in myeloid cells. USP18 isopeptidase activity assays, ISG15 knockdown in primary myeloid cells, p53 conformation assays, HIV-1 replication assays mBio Medium 31455647
2020 Intracellular ISGylation inhibits ISG15 secretion, while influenza B NS1 (which sequesters ISG15) and viral de-ISGylases (including SARS-CoV-2 PLpro) have opposing effects on ISG15 secretion. Both epithelial cells and lymphocytes can secrete ISG15 to signal in autocrine or paracrine fashion through LFA-1. ISG15 secretion assays, ISGylation inhibition experiments, viral effector protein expression, residue mapping of secretion-critical ISG15 residues Cell reports Medium 32553163
2021 IRF3 drives expression of ISG15, which becomes covalently attached (ISGylated) to glycolytic enzymes in adipocytes, reducing their enzymatic function and decreasing lactate production. Reduced lactate suppresses thermogenic gene expression. ISG15-deficient mice phenocopy adipocyte-specific IRF3-deficient mice with elevated energy expenditure and resistance to diet-induced obesity. Isg15 knockout mice, IRF3 overexpression/knockout in adipocytes, metabolic measurements (oxygen consumption, energy expenditure), lactate repletion rescue experiments, ISGylation assays of glycolytic enzymes The Journal of clinical investigation High 33571167
2020 ISG15 deletion in pancreatic cancer stem cells (PaCSCs) decreases mitochondrial ISGylation, impairs mitophagy, reduces oxidative phosphorylation, and impairs self-renewal and tumorigenic capacity. Rescue with wild-type ISG15 but not conjugation-deficient ISG15 restored these functions, indicating ISGylation (not free ISG15) is required for mitophagy and metabolic plasticity. CRISPR-mediated ISG15 KO, complementation with WT vs. conjugation-deficient ISG15, mitochondrial function assays (OXPHOS, mitophagy), in vivo tumor formation assays Nature communications High 32472071
2023 ISGylation of STING at residue K289 is required for STING oligomerization and type I IFN induction in response to HIV-1 DNA sensing via cGAS-STING. ISG15 deficiency inhibits STING-dependent antiviral sensing. Removal of STING ISGylation alleviates gain-of-function phenotype in SAVI disease. ISG15 KO cells, site-directed mutagenesis of STING ISGylation sites (K224, K236, K289, K347, K338, K370), STING oligomerization assays, IFN induction assays, molecular modeling Cell reports Medium 37864791
2020 ISG15 and ISGylation are required for IFN-γ-mediated restriction of Toxoplasma gondii in human cells. ISG15 deletion impaired recruitment of autophagy adaptors p62, NDP52, and LC3 to the parasitophorous vacuole. ISG15 function required conjugation, and ISGylated targets overlapped with the IFN-γ-dependent ATG5 interactome, including adapter p62. ISG15 KO HeLa cells, proximity biotinylation of ATG5 interactome, immunofluorescence of p62/NDP52/LC3 recruitment, T. gondii growth restriction assays, conjugation-deficient ISG15 rescue mBio Medium 33024031
2015 ISG15 expression restricts Listeria monocytogenes infection in vitro and in vivo. ISG15 induction in non-phagocytic cells upon Listeria infection can be type I IFN-independent, signaling through STING-TBK1-IRF3/IRF7 cytosolic DNA surveillance pathway. ISGylation of ER and Golgi proteins correlates with increased secretion of anti-infection cytokines. ISG15 overexpression and knockout cells, SILAC proteomics to identify ISGylated proteins, in vivo Listeria infection model, IFN pathway inhibition eLife Medium 26259872
2007 UbcH8 (the ISG15 E2 enzyme) competes with RNF125 ubiquitin E3 ligase for RIG-I modification: UbcH8 suppresses RIG-I ubiquitination by RNF125, and this suppression is relieved by ectopic ISG15. Conversely, ISG15 conjugation to RIG-I is suppressed by RNF125. UbcH8 and ISG15 function as regulators of RNF125 E3 ligase activity toward RIG-I. Co-immunoprecipitation, ectopic expression of UbcH8/ISG15/RNF125, ubiquitination and ISGylation assays for RIG-I Molecular immunology Medium 17719635
2016 HCMV pUL26 interacts with ISG15, UBE1L (E1), and HERC5 (E3), and is itself ISGylated. ISGylation of pUL26 regulated its stability and inhibited its activities (NF-κB suppression and viral growth complementation). Reciprocally, pUL26 suppressed virus-induced ISGylation independent of its own ISGylation. ISGylation inhibits HCMV growth by downregulating viral gene expression and virion release. Co-immunoprecipitation, ISGylation assays, RNAi knockdown of ISGylation enzymes, UL26-null mutant virus analysis, NF-κB reporter assay PLoS pathogens Medium 27564865
2022 ISG15 conjugation to proteins on nascent DNA mitigates DNA replication stress. Mre11 complex inactivation causes cGAS-STING-TBK1-dependent ISG15 induction and ISGylation of replication fork constituents. ISG15 deletion is associated with replication fork stalling, tonic ATR activation, genomic aberrations, and sensitivity to aphidicolin. Mre11 complex inactivation, ISG15 deletion mouse cells, iPOND (isolation of proteins on nascent DNA), replication fork stability assays, aphidicolin sensitivity, cGAS-STING signaling assays Nature communications Medium 36216822
2019 USP18 and ISG15 regulate the SCF-SKP2 ubiquitin E3 ligase complex: free ISG15 disrupts the USP18-SKP2 interaction, liberating USP18 from SKP2-mediated degradation while simultaneously driving SKP2 to degradation and/or ISGylation. USP18 silencing slows HeLa S3 cell progression toward S phase. Co-immunoprecipitation of USP18-SKP2 complex, ectopic ISG15 expression, cell cycle analysis, USP18 siRNA knockdown Scientific reports Medium 30858391
2017 ISG15 directly conjugates to PTEN (ISGylation of PTEN), and USP18 deISGylase stabilizes PTEN protein. USP18 knockdown destabilizes PTEN while USP18 overexpression stabilizes PTEN. USP18 repression decreased cytoplasmic relative to nuclear PTEN levels. Co-immunoprecipitation showing ISG15-PTEN conjugation, cycloheximide chase assays, reverse-phase protein arrays, USP18 knockdown/overexpression Oncotarget Medium 27980214
2020 ISGylation of viral and host proteins (including antiviral IFIT1/3 proteins) by ISG15 sets non-hematopoietic cells into a state resistant to coxsackievirus B3 (CVB). Concurrently, ISG15 adapts liver metabolism by increasing oxidative capacity and promoting gluconeogenesis. Cells lacking USP18 (thereby stabilizing ISGylation) show increased resistance to CVB. ISG15 KO and USP18 KO mouse models, shotgun proteomics, metabolic network modeling, coxsackievirus infection assays Science advances Medium 32195343
2024 ISGylation of hexokinase 2 (HK2) and phosphofructokinase (PFK1) during Coxsackievirus B3 infection obstructs their enzymatic activity, preventing infection/IFN-induced upregulation of glycolysis in cardiomyocytes. This preserves mitochondrial oxidative capacity in the heart during infection. Mass spectrometry ISGylome identification, enzymatic functional testing of HK2 and PFK1, structural modeling, Seahorse metabolic flux analysis in cardiomyocytes and mouse heart tissue, ISG15 KO mice Cardiovascular research Medium 38309955
2023 ISG15 upregulation in pressure-overloaded hearts (driven by type I IFN signaling from pathogenic macrophages) leads to ISGylation of the myofibrillar protein filamin-C, promoting misfolded filamin-C accumulation and impairing cardiomyocyte autophagy, contributing to adverse ventricular remodeling. ISG15 deficiency preserved cardiac function in transverse aortic constriction mice. Nanoscale LC-MS/MS to identify ISGylation targets, ISG15 KO mice with TAC model, cardiac function measurements, metabolomics, human nonischemic cardiomyopathy tissue analysis The Journal of clinical investigation Medium 37115698
2023 USP16 functions as an ISG15 cross-reactive deubiquitinase. Recombinant USP16 cleaved pro-ISG15 and ISG15 isopeptide-linked substrates in vitro and from cell lysates; USP16 depletion increased interferon-induced ISGylation. USP16-dependent ISG15 substrates include malate dehydrogenase, superoxide dismutase 1, fructose-bisphosphate aldolase A, and glutamic-oxaloacetic transaminase 1. ISG15 activity-based profiling, recombinant USP16 in vitro cleavage assays, USP16 depletion and ISGylation measurement, ISG15 interactome analysis Proceedings of the National Academy of Sciences of the United States of America Medium 38055744
2017 USP18 is a highly specific protease that cleaves ISG15 from ISGylated proteins. Crystal structures of USP18 and a USP18-ISG15 complex revealed the molecular basis for its unique specificity for ISG15 over ubiquitin. USP18 also interacts with the type I IFN receptor to shut off downstream signaling independent of its enzymatic activity. Crystal structure of USP18-ISG15 complex, biochemical cleavage assays The FEBS journal Medium 28881486
2016 ISG15 ISGylation of RSV-infected cells reduces virus growth. Conjugation inhibition assays demonstrated that the antiviral activity against RSV requires protein ISGylation (not free ISG15). High levels of ISG15 present before infection are required for antiviral activity. ISG15 overexpression, siRNA silencing, ISG15 KO cells, conjugation inhibition assays, RSV growth assays Journal of virology Medium 26763998
2023 ISGylation of KPNA2 (importin subunit alpha 2) by ISG15 impedes KPNA2 ubiquitination, promoting KPNA2 stability, which in turn maintains cancer stem cell-like characteristics in anaplastic thyroid carcinoma. Overexpression of ISGylation-competent but not non-ISGylatable ISG15 mutant reinforced CSC characteristics. Mass spectrometry to identify ISGylation substrates, co-immunoprecipitation, ISGylation-deficient ISG15 mutant rescue, KPNA2 ubiquitination assay, xenograft models Journal of experimental & clinical cancer research : CR Medium 37501099
2023 ISG15 promotes ISGylation-mediated degradation of glycosylated PD-L1 via K48-linked ubiquitin chains targeting the proteasomal pathway, reducing PD-L1 protein stability in lung adenocarcinoma cells. Co-immunoprecipitation showing ISG15-PD-L1 conjugation, K48-ubiquitin chain analysis, Western blot, in vivo mouse models, flow cytometry Journal of translational medicine Low 37217923
2022 ISG15 and ISGylation are required for optimal mitochondrial respiration; defective mitochondrial respiration in ISG15-/- macrophages is restored by transduction with wild-type ISG15 but only partially by a conjugation-deficient variant, indicating that mitochondrial respiratory function requires ISGylation to cellular targets. iPSC-derived macrophages from ISG15-deficient patients, complementation with WT vs. conjugation-deficient ISG15, mitochondrial respiration assays, metabolic profiling Clinical and translational medicine Medium 35842904
2022 Free ISG15 (unconjugated) promotes type I IFN-α-mediated antiviral activity against pseudorabies virus by facilitating STAT1 and STAT2 nuclear translocation, directly interacting with STAT2, and promoting ISGF3 (STAT1/STAT2/IRF9) complex formation and ISRE-driven gene transcription. ISG15 KO cell lines and mice, conjugation inhibition assays, co-immunoprecipitation of ISG15-STAT2 interaction, ISGF3 formation assay, ISRE luciferase reporter, nuclear fractionation PLoS pathogens Medium 36315588
2024 PARP12 interacts with ISG15 and upregulates MFN1/2 ISGylation, which reduces MFN1/2 ubiquitination and SUMOylation, thereby inhibiting PINK1/Parkin-dependent mitophagy in chondrocytes and promoting cartilage degradation in osteoarthritis. Mass spectrometry, co-immunoprecipitation of PARP12-ISG15 interaction, ISGylation, ubiquitination, and SUMOylation assays for MFN1/2, mitophagy assays, rat OA model Bone research Medium 39465252
2023 ISG15 restricts Dengue and Zika virus replication by stabilizing USP18 protein. ISG15-dependent USP18 stability prevents NS5-mediated STAT2 degradation. Reconstitution of USP18 in ISG15-deficient cells restored STAT2 stability and restricted virus growth. ISG15-deficient cells, USP18 reconstitution, STAT2 stability assays, dengue/Zika viral replication assays Frontiers in immunology Medium 38384473
2023 IFNβ restores replication fork stability in BRCA1/2-deficient cells in a manner that strictly depends on ISG15 and ISGylation. Basal ISG15 levels protect nascent DNA from degradation. ISG15 depletion reduces cell proliferation in BRCA1-mutated triple-negative breast cancer cells, and ISG15 upregulation increases resistance to cisplatin in BRCA2-deficient cells. ISG15 siRNA/KO, IFNβ treatment, DNA fiber assays for replication fork protection, BRCA1/2-deficient mouse embryonic stem cells and human cancer cells, ISGylation complementation Nature communications Medium 37783689
2022 ISG15-deficient skin fibroblasts and keratinocytes show impaired cell migration, reduced collagen and integrin synthesis, increased matrix metalloproteinases, and elevated ROS with reduced ROS scavenger expression. Defective collagen and integrin synthesis was not rescued by conjugation-deficient ISG15, while hyperinflammation was rescued by ruxolitinib. ISG15-deficient patient fibroblasts, HaCaT keratinocytes, iPSC-derived endothelial cells, complementation with WT vs. conjugation-deficient ISG15, migration assays, 3D epidermis model, ruxolitinib treatment The Journal of clinical investigation Medium 34847081
2018 ISG15 promotes ISGylation of ERK1, and this ISGylation suppresses ovarian cancer progression. Endogenous and exogenous ISG15 suppressed ovarian cancer progression through ISGylation of ERK. ISG15 also activated NK cells and CD8+ T lymphocytes. Transcriptome profiling of microdissected tumor tissue, ISGylation assays for ERK, functional assays with endogenous/exogenous ISG15 in ovarian cancer cell lines, NK and CD8+ T cell activation assays Cancers Low 30469497
2024 DRD4 (dopamine D4 receptor) reduces ISG15 expression, which in turn suppresses NOX4 ISGylation; reduced NOX4 ISGylation promotes its ubiquitination and degradation, counteracting oxidative stress in acute kidney injury. Transcriptome sequencing, DRD4 KO and overexpression in mouse IRI model, NOX4 ISGylation and ubiquitination assays, ROS measurement Redox biology Low 38354631
2014 ISG15 promotes HCC cell proliferation and migration by maintaining Survivin protein stabilization via sequestering XIAP from interacting with Survivin. ISG15 siRNA knockdown, xenograft tumor model, co-immunoprecipitation assays for ISG15-XIAP-Survivin interactions Oncotarget Low 25238261

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 ISG15 in antiviral immunity and beyond. Nature reviews. Microbiology 667 29769653
2012 Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency. Science (New York, N.Y.) 446 22859821
2013 The antiviral activities of ISG15. Journal of molecular biology 208 24095857
2017 Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor. Molecular cell 193 29100055
2006 Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway. Cancer research 172 16424026
2016 ISG15 deficiency and increased viral resistance in humans but not mice. Nature communications 164 27193971
2010 ISG15 and immune diseases. Biochimica et biophysica acta 140 20153823
2019 ISG15: It's Complicated. Journal of molecular biology 138 30890331
2004 ISG15: the immunological kin of ubiquitin. Seminars in cell & developmental biology 114 15209384
2020 ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity. Nature communications 111 32472071
2015 ISG15 counteracts Listeria monocytogenes infection. eLife 110 26259872
2013 Interferon-induced ISG15 pathway: an ongoing virus-host battle. Trends in microbiology 108 23414970
2005 ISG15: a ubiquitin-like enigma. Frontiers in bioscience : a journal and virtual library 106 15970528
2013 Molecular cloning, expression and functional analysis of ISG15 in orange-spotted grouper, Epinephelus coioides. Fish & shellfish immunology 97 23403156
2013 ISG15: leading a double life as a secreted molecule. Experimental & molecular medicine 97 23579383
2022 ISG15 and ISGylation in Human Diseases. Cells 96 35159348
1999 Precursor processing of pro-ISG15/UCRP, an interferon-beta-induced ubiquitin-like protein. The Journal of biological chemistry 96 10455185
2016 ISG15: In Sickness and in Health. Trends in immunology 91 27887993
2014 Interferon-stimulated gene 15 (ISG15) is a trigger for tumorigenesis and metastasis of hepatocellular carcinoma. Oncotarget 85 25238261
2009 Telomere length regulates ISG15 expression in human cells. Aging 81 20157543
2017 Beyond ISGlylation: Functions of Free Intracellular and Extracellular ISG15. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 80 28467275
2009 Antiviral activity of innate immune protein ISG15. Journal of innate immunity 79 19680460
2020 Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins. Cell reports 76 32553163
2018 ISG15 in cancer: Beyond ubiquitin-like protein. Cancer letters 76 30213559
2022 The diverse repertoire of ISG15: more intricate than initially thought. Experimental & molecular medicine 74 36319753
2021 IRF3 reduces adipose thermogenesis via ISG15-mediated reprogramming of glycolysis. The Journal of clinical investigation 74 33571167
2020 Intestinal Epithelial Cells Express Immunomodulatory ISG15 During Active Ulcerative Colitis and Crohn's Disease. Journal of Crohn's & colitis 70 32020185
2020 Tumor Cell-Secreted ISG15 Promotes Tumor Cell Migration and Immune Suppression by Inducing the Macrophage M2-Like Phenotype. Frontiers in immunology 69 33424843
2006 The interferon regulated ubiquitin-like protein, ISG15, in tumorigenesis: friend or foe? Cytokine & growth factor reviews 68 17097911
2014 Isg15 controls p53 stability and functions. Cell cycle (Georgetown, Tex.) 65 24844324
2016 ISG15 Is Upregulated in Respiratory Syncytial Virus Infection and Reduces Virus Growth through Protein ISGylation. Journal of virology 62 26763998
2020 How ISG15 combats viral infection. Virus research 61 32492472
2003 ISG15, not just another ubiquitin-like protein. Biochemical and biophysical research communications 60 12893238
2016 Consecutive Inhibition of ISG15 Expression and ISGylation by Cytomegalovirus Regulators. PLoS pathogens 59 27564865
2023 Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin. Nature communications 55 37185902
2020 ISG15 Connects Autophagy and IFN-γ-Dependent Control of Toxoplasma gondii Infection in Human Cells. mBio 53 33024031
2011 The ISG15/USP18 ubiquitin-like pathway (ISGylation system) in hepatitis C virus infection and resistance to interferon therapy. The international journal of biochemistry & cell biology 53 21704181
2016 ISG15 inhibits cancer cell growth and promotes apoptosis. International journal of molecular medicine 52 28035359
2007 Viral defense, carcinogenesis and ISG15: novel roles for an old ISG. Cytokine & growth factor reviews 51 17689132
2004 Camptothecin induces the ubiquitin-like protein, ISG15, and enhances ISG15 conjugation in response to interferon. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 50 15684817
2020 More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond. Biomolecules 49 33203188
2007 UbcH8 regulates ubiquitin and ISG15 conjugation to RIG-I. Molecular immunology 49 17719635
2010 Antiviral Properties of ISG15. Viruses 46 21994614
2017 The ISG15-specific protease USP18 regulates stability of PTEN. Oncotarget 45 27980214
2022 ISG15 conjugation to proteins on nascent DNA mitigates DNA replication stress. Nature communications 44 36216822
2020 Strategies to Target ISG15 and USP18 Toward Therapeutic Applications. Frontiers in chemistry 44 32039148
2020 Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming. Science advances 44 32195343
2018 ISG15, a Small Molecule with Huge Implications: Regulation of Mitochondrial Homeostasis. Viruses 44 30428561
2018 Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target. Cancer research 43 29343520
2023 ISG15: its roles in SARS-CoV-2 and other viral infections. Trends in microbiology 41 37573184
2023 ISG15 targets glycosylated PD-L1 and promotes its degradation to enhance antitumor immune effects in lung adenocarcinoma. Journal of translational medicine 38 37217923
2016 ISG15 in the tumorigenesis and treatment of cancer: An emerging role in malignancies of the digestive system. Oncotarget 38 27626310
2015 ISG15 expression correlates with HIV-1 viral load and with factors regulating T cell response. Immunobiology 38 26563749
2023 The Functional Roles of ISG15/ISGylation in Cancer. Molecules (Basel, Switzerland) 37 36771004
2013 Emerging roles for immunomodulatory functions of free ISG15. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 36 24010825
2023 Regulation of STING activity in DNA sensing by ISG15 modification. Cell reports 35 37864791
2019 USP18 and ISG15 coordinately impact on SKP2 and cell cycle progression. Scientific reports 35 30858391
2017 UBE2L6/UBCH8 and ISG15 attenuate autophagy in esophageal cancer cells. Oncotarget 35 28186990
2018 ISG15 Promotes ERK1 ISGylation, CD8+ T Cell Activation and Suppresses Ovarian Cancer Progression. Cancers 34 30469497
2021 ISG15 is downregulated by KLF12 and implicated in maintenance of cancer stem cell-like features in cisplatin-resistant ovarian cancer. Journal of cellular and molecular medicine 33 33797839
2012 The ISG15 conjugation system. Methods in molecular biology (Clifton, N.J.) 33 22350882
2022 WBSCR22 and TRMT112 synergistically suppress cell proliferation, invasion and tumorigenesis in pancreatic cancer via transcriptional regulation of ISG15. International journal of oncology 32 35088887
2017 Roles of miR-138 and ISG15 in oral squamous cell carcinoma. Experimental and therapeutic medicine 32 28962163
2018 ISG15 promotes esophageal squamous cell carcinoma tumorigenesis via c-MET/Fyn/β-catenin signaling pathway. Experimental cell research 31 29555370
2022 ISG15 deficiency features a complex cellular phenotype that responds to treatment with itaconate and derivatives. Clinical and translational medicine 30 35842904
2022 Congenital deficiency reveals critical role of ISG15 in skin homeostasis. The Journal of clinical investigation 29 34847081
2022 Free ISG15 inhibits Pseudorabies virus infection by positively regulating type I IFN signaling. PLoS pathogens 29 36315588
2019 ISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p53. mBio 29 31455647
2024 Unveiling the Multifaceted Roles of ISG15: From Immunomodulation to Therapeutic Frontiers. Vaccines 28 38400136
2023 Interferon stimulated gene 15 (ISG15) in cancer: An update. Cancer letters 27 36736853
2023 Pressure overload induces ISG15 to facilitate adverse ventricular remodeling and promote heart failure. The Journal of clinical investigation 27 37115698
2017 Cell type-dependent regulation of free ISG15 levels and ISGylation. Journal of cell communication and signaling 27 28285335
2024 DRD4 alleviates acute kidney injury by suppressing ISG15/NOX4 axis-associated oxidative stress. Redox biology 26 38354631
2023 ISG15 and ISGylation modulates cancer stem cell-like characteristics in promoting tumor growth of anaplastic thyroid carcinoma. Journal of experimental & clinical cancer research : CR 26 37501099
2022 ISG15 deficiency restricts HIV-1 infection. PLoS pathogens 25 35333911
2013 ISG15 inhibits IFN-α-resistant liver cancer cell growth. BioMed research international 25 24024201
2020 ISG15 induces ESRP1 to inhibit lung adenocarcinoma progression. Cell death & disease 24 32641707
2013 Interferon stimulated gene-ISG15 is a potential diagnostic biomarker in oral squamous cell carcinomas. Asian Pacific journal of cancer prevention : APJCP 24 23621203
2023 Cryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer. Nature communications 23 37553340
2022 ISG15 driven cellular responses to virus infection. Biochemical Society transactions 23 36416643
2022 ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection. Microbiology spectrum 23 36453897
2024 ISG15 blocks cardiac glycolysis and ensures sufficient mitochondrial energy production during Coxsackievirus B3 infection. Cardiovascular research 22 38309955
2022 Preeclampsia is Associated With Reduced ISG15 Levels Impairing Extravillous Trophoblast Invasion. Frontiers in cell and developmental biology 22 35837332
2017 ISG15 silencing increases cisplatin resistance via activating p53-mediated cell DNA repair. Oncotarget 22 29296177
2024 IRF1-mediated upregulation of PARP12 promotes cartilage degradation by inhibiting PINK1/Parkin dependent mitophagy through ISG15 attenuating ubiquitylation and SUMOylation of MFN1/2. Bone research 21 39465252
2023 USP16 is an ISG15 cross-reactive deubiquitinase that targets pro-ISG15 and ISGylated proteins involved in metabolism. Proceedings of the National Academy of Sciences of the United States of America 21 38055744
2022 Coronaviral PLpro proteases and the immunomodulatory roles of conjugated versus free Interferon Stimulated Gene product-15 (ISG15). Seminars in cell & developmental biology 21 35764457
2017 How USP18 deals with ISG15-modified proteins: structural basis for the specificity of the protease. The FEBS journal 21 28881486
2014 Human rhinovirus-induced ISG15 selectively modulates epithelial antiviral immunity. Mucosal immunology 21 24448099
2023 Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15. Nature communications 20 37783689
2023 Insights into the ISG15 transfer cascade by the UBE1L activating enzyme. Nature communications 20 38042859
2018 The Overexpression of CD80 and ISG15 Are Associated with the Progression and Metastasis of Breast Cancer by a Meta-Analysis Integrating Three Microarray Datasets. Pathology oncology research : POR 20 30411299
2010 Identification and Validation of ISG15 Target Proteins. Sub-cellular biochemistry 20 21222286
2005 Down-regulation of UCRP and UBE2L6 in BRCA2 knocked-down human breast cells. Biochemical and biophysical research communications 20 15670748
2024 cGAS-ISG15-RAGE axis reprogram necroptotic microenvironment and promote lymphatic metastasis in head and neck cancer. Experimental hematology & oncology 19 38926796
2018 miR-370 regulates ISG15 expression and influences IFN-α sensitivity in hepatocellular carcinoma cells. Cancer biomarkers : section A of Disease markers 19 29758929
2023 ISG15: A link between innate immune signaling, DNA replication, and genome stability. BioEssays : news and reviews in molecular, cellular and developmental biology 18 37147792
2024 ISG15/USP18/STAT2 is a molecular hub regulating IFN I-mediated control of Dengue and Zika virus replication. Frontiers in immunology 17 38384473
2022 Expedient Synthesis of Ubiquitin-like Protein ISG15 Tools through Chemo-Enzymatic Ligation Catalyzed by a Viral Protease Lbpro. Angewandte Chemie (International ed. in English) 17 35962463
2018 Protein ISGylation and free ISG15 levels are increased by interferon gamma in breast cancer cells. Biochemical and biophysical research communications 17 29626479

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