Affinage

USP18

Ubl carboxyl-terminal hydrolase 18 · UniProt Q9UMW8

Length
372 aa
Mass
43.0 kDa
Annotated
2026-06-11
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP18 is a dual-function regulator of type I interferon biology that combines an ISG15-specific protease activity with a catalytically-independent scaffolding role at the interferon receptor (PMID:11788588, PMID:25605921). As an isopeptidase it is the major in vivo deconjugase that removes ISG15 from substrates, with essentially no activity toward ubiquitin, SUMO, or NEDD8; loss of USP18 causes massive accumulation of ISG15 conjugates (PMID:11788588). Crystallographic and mutational analysis defines its ISG15 specificity: USP18 recognizes only the C-terminal ubiquitin-like domain of ISG15 through a hydrophobic patch absent from ubiquitin (PMID:28165509). Independently of catalysis, USP18 functions as a negative-feedback brake on type I IFN signaling: STAT2 recruits USP18 to the IFNAR2 receptor subunit, where it sterically blocks JAK1 access and impairs assembly of functional IFN-binding sites, producing long-lasting desensitization of JAK-STAT signaling in vivo (PMID:28165510, PMID:21779393, PMID:19564419, PMID:32092142, PMID:31940699). Catalytic-dead knock-in mice and patient-derived variants dissect these two activities, showing that suppression of IFN signaling and prevention of IFN hypersensitivity require the STAT2/IFNAR2 scaffold function rather than enzymatic activity, while enhanced ISGylation and antiviral resistance require the isopeptidase (PMID:25605921, PMID:35258551, PMID:38632987). This scaffold function maintains microglial quiescence against tonic IFN signaling (PMID:25896511). Beyond interferon, USP18 deubiquitinates components of innate immune and inflammatory signaling — removing K63-linked chains from TAK1 to restrain NF-κB/NFAT and Th17-driven autoimmunity (PMID:23825189, PMID:28718215), binding NEMO to limit IKK activation (PMID:26240016), and acting as a scaffold to recruit USP20 to deubiquitinate and stabilize STING and to re-localize TRIM31 to mitochondria to potentiate MAVS (PMID:27801882, PMID:34016972). Its own stability is governed by ISG15, which competes with SKP2 to protect USP18 from SCF-SKP2–mediated proteasomal degradation (PMID:30858391). In tumor and tissue contexts USP18 deubiquitinates and stabilizes a broad set of substrates including Notch1, Twist1, ZEB1, SOX9, cGAS, SLC7A11, FTO, PTEN, and FOXO3a to modulate EMT, ferroptosis, metabolic, and survival programs (PMID:33051403, PMID:32368392, PMID:34743935, PMID:33694203, PMID:37478666, PMID:38959043, PMID:38340205, PMID:27980214, PMID:31874933).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 2000 Medium

    Established the basic identity of USP18 as a USP-family deubiquitinating enzyme and its nuclear localization, providing the molecular starting point.

    Evidence cDNA cloning and immunofluorescence of tagged constructs in transfected human cells

    PMID:10777664

    Open questions at the time
    • Did not define substrate specificity
    • Did not address non-nuclear isoforms or functions
  2. 2002 High

    Resolved what USP18 actually cleaves, identifying it as the major ISG15-specific protease rather than a general deubiquitinase.

    Evidence In vitro protease assays with multiple Ubl substrates, self-processing assay, and USP18 knockout mouse

    PMID:11788588

    Open questions at the time
    • Did not explain the structural basis for ISG15 over ubiquitin selectivity
    • Did not address non-catalytic functions
  3. 2006 Medium

    Linked USP18 to the antiviral IFN response by showing its knockdown potentiates IFN-α suppression of HCV replication.

    Evidence siRNA knockdown with HCV replicon/virus and STAT1 phosphorylation readouts in human cells

    PMID:17101330

    Open questions at the time
    • Did not separate ISGylation effects from receptor-level signaling effects
    • Single-lab loss-of-function
  4. 2009 High

    Identified USP18 as the dominant mediator of sustained, long-lasting refractoriness of IFN-α JAK-STAT signaling in vivo, distinct from SOCS-mediated early termination.

    Evidence Repeated IFN-α injection with genetic epistasis across USP18, SOCS1, and SOCS3 knockout mice

    PMID:19564419

    Open questions at the time
    • Did not define the molecular mechanism at the receptor
    • Did not establish whether catalytic activity is required
  5. 2011 High

    Localized USP18's negative regulation to the receptor level, showing it impairs IFN-α2 binding-site formation at IFNAR2 and underlies differential IFN desensitization.

    Evidence Overexpression/RNAi with receptor-binding and signaling readouts in cell lines

    PMID:21779393

    Open questions at the time
    • Did not identify the adaptor recruiting USP18 to the receptor
    • Did not resolve catalytic requirement
  6. 2011 Medium

    Revealed alternative translation initiation producing a nuclear short isoform with enhanced deISGylation activity, indicating isoform-specific functional compartmentalization.

    Evidence Start-codon mutagenesis, IRES reporter assays, fractionation, and in vitro deISGylation comparing isoforms

    PMID:22170061

    Open questions at the time
    • Physiological role of the short isoform not established in vivo
    • Single-study observation
  7. 2015 High

    Genetically separated USP18's two activities, proving that suppression of IFN signaling is catalysis-independent while ISGylation and antiviral resistance require the isopeptidase.

    Evidence Catalytically inactive C61A knock-in mice with ISG15 KO epistasis and viral challenge

    PMID:25605921

    Open questions at the time
    • Did not define the scaffold molecular mechanism
    • Did not map the protein interface used for non-catalytic function
  8. 2015 High

    Demonstrated that USP18's catalysis-independent, IFNAR2-dependent function maintains microglial quiescence against tonic IFN signaling.

    Evidence Microglia-conditional Usp18 KO with IFNAR1/IFNAR2 epistasis and catalytic-inactive rescue

    PMID:25896511

    Open questions at the time
    • Did not define the receptor-proximal molecular block
    • Source of tonic IFN not identified
  9. 2013 High

    Identified TAK1 as a catalytic substrate, linking USP18 to NF-κB/NFAT restraint and Th17-driven autoimmunity.

    Evidence Co-IP, in vitro deubiquitination, USP18 KO T cells, and EAE model

    PMID:23825189

    Open questions at the time
    • Did not address whether scaffold or catalytic mechanism dominates in other cell types
  10. 2015 Medium

    Showed USP18 uses two distinct mechanisms against NF-κB: protease-dependent TAK1 deubiquitination and protease-independent NEMO/UBAN binding.

    Evidence Co-IP, in vitro DUB assay, and UBAN-binding mutation analysis in human macrophages

    PMID:26240016

    Open questions at the time
    • NEMO interface not structurally defined
    • Single-lab study
  11. 2016 High

    Established USP18 as a scaffold that recruits a partner DUB (USP20) to stabilize STING, defining a non-catalytic mode of substrate deubiquitination.

    Evidence Reciprocal Co-IP, in vitro DUB assay, KO rescue, and in vivo HSV-1 infection

    PMID:27801882

    Open questions at the time
    • Did not define how USP18 selects USP20 over other DUBs
    • Structural basis of the ternary complex unknown
  12. 2017 High

    Provided the structural basis for ISG15 specificity, showing USP18 recognizes only the C-terminal Ubl domain via a hydrophobic patch.

    Evidence X-ray crystallography of USP18 alone and USP18–ISG15 with mutational validation

    PMID:28165509

    Open questions at the time
    • Structures are of mouse protein; human catalytic weakness not yet structurally explained
    • Did not capture the STAT2/IFNAR2 scaffold interface
  13. 2017 High

    Identified STAT2 as the essential adaptor recruiting USP18 to IFNAR2, explaining how the catalysis-independent feedback is targeted to the receptor.

    Evidence Reciprocal Co-IP and functional reconstitution in human and mouse cells

    PMID:28165510

    Open questions at the time
    • Did not yet show the JAK1-blocking step directly
    • STAT2-binding interface on USP18 not mapped
  14. 2017 Medium

    Extended USP18 substrate range to PTEN, showing deISGylation stabilizes cytoplasmic PTEN.

    Evidence RPPA, CHX chase, Co-IP for ISG15-PTEN conjugation, and fractionation with KD/OE

    PMID:27980214

    Open questions at the time
    • In vivo relevance not established
    • Single-lab study
  15. 2017 High

    Demonstrated a catalysis-dependent metabolic role: USP18 deubiquitinates TAK1 to protect against hepatic steatosis and insulin resistance.

    Evidence Co-IP, in vitro DUB assay, hepatocyte-specific transgenic/KO mice, and active-site mutant rescue

    PMID:28718215

    Open questions at the time
    • Did not reconcile catalytic requirement here with catalysis-independent TAK1/NEMO mechanisms reported elsewhere
  16. 2019 Medium

    Defined the regulation of USP18 stability, showing ISG15 protects USP18 from SKP2-dependent proteasomal degradation in a reciprocal relationship linked to cell cycle progression.

    Evidence Co-IP, OE/silencing, proteasome inhibition, and flow cytometry cell cycle analysis

    PMID:30858391

    Open questions at the time
    • Direct cell-cycle substrate of USP18 not identified
    • Single-lab study
  17. 2019 Medium

    Added FOXO3a as a deISGylation target, linking USP18 to fibrosis signaling.

    Evidence ISGylation assays, CHX chase, proteasome inhibition, and fibronectin readout in lung fibroblasts

    PMID:31874933

    Open questions at the time
    • In vivo fibrosis role not tested
    • Single-lab study
  18. 2020 High

    Resolved the receptor-level mechanism, showing USP18 sterically blocks JAK1 access to IFNAR2 and that a patient STAT2 R148Q mutation phenocopies USP18 deficiency by failing to traffic USP18.

    Evidence Patient mutation analysis with functional complementation and signaling assays in patient cells

    PMID:31940699 PMID:32092142

    Open questions at the time
    • Atomic structure of the USP18–IFNAR2–JAK1 arrangement not resolved
  19. 2020 Medium

    Showed nuclear USP18 shapes the cancer enhancer landscape and limits STAT2-driven ISG/NF-κB transcription, with depletion triggering pyroptosis.

    Evidence ChIP-seq/ATAC-seq, USP18 KO in cancer lines, transcriptomics, and pyroptosis assays

    PMID:36646704

    Open questions at the time
    • Mechanism connecting nuclear USP18 to chromatin not defined
    • Single-lab study
  20. 2020 Medium

    Connected USP18/SKP2 to p21 and SAMHD1 regulation, promoting HIV-1 reverse transcription in myeloid cells.

    Evidence Co-IP, CRISPR KO, dNTP and SAMHD1 phosphorylation assays, HIV-1 replication

    PMID:30068654

    Open questions at the time
    • Direct biochemical link between USP18 and p21 turnover not established
    • Single-lab study
  21. 2021 High

    Defined a mitochondrial scaffold function in which USP18 re-localizes TRIM31 to potentiate MAVS-dependent antiviral IFN, independent of enzymatic activity.

    Evidence Reciprocal Co-IP, ubiquitination assays, fractionation, and Usp18 KO mice with SeV/EMCV

    PMID:34016972

    Open questions at the time
    • How USP18 partitions between receptor, mitochondria, and nucleus not resolved
  22. 2021 Medium

    Showed USP18 stabilizes SOX9 to drive reactive astrogliosis and is itself a Hedgehog/Gli2 transcriptional target.

    Evidence Co-IP, ubiquitination assay, astrocyte-conditional KO, AAV overexpression, and ChIP

    PMID:33694203

    Open questions at the time
    • Catalytic vs scaffold requirement for SOX9 stabilization not dissected
    • Single-lab study
  23. 2022 High

    Used a patient I60N variant to prove the STAT2-binding scaffold interface is functionally separable from the catalytic domain and from ISG15-mediated stabilization.

    Evidence Patient variant analysis, Co-IP with STAT2/IFNAR2, ISG15 stabilization, and signaling assays

    PMID:35258551

    Open questions at the time
    • Atomic mapping of the STAT2-binding surface not provided
  24. 2023 Medium

    Expanded oncogenic substrate stabilization, with USP18 deubiquitinating Notch1, ZEB1, and cGAS to promote tumor progression, EMT, and drug resistance.

    Evidence Co-IP, K48-chain ubiquitination assays, and in vivo xenograft/metastasis models

    PMID:33051403 PMID:34743935 PMID:37422930 PMID:37478666

    Open questions at the time
    • Catalytic vs scaffold mechanism not consistently dissected across substrates
    • Each link rests on single-lab studies
  25. 2023 Medium

    Linked USP18 to RNA epigenetics, stabilizing FTO to lower m6A on SIRT6 mRNA and drive neuroprotective mitophagy.

    Evidence Co-IP, MeRIP/RIP m6A assays, OGD/R and MCAO models with epistasis

    PMID:38340205

    Open questions at the time
    • Direct deubiquitination biochemistry on FTO limited
    • Single-lab study
  26. 2024 High

    Resolved the long-standing catalytic-vs-scaffold question for human USP18, showing human enzyme has minimal ISG15-cleaving activity and that the scaffold function drives cancer cell IFN vulnerability.

    Evidence Biochemical human vs mouse activity assays and I60N vs C64S mutant comparison with cellular readouts

    PMID:38632987

    Open questions at the time
    • Structural explanation for weak human catalysis not provided
  27. 2024 Medium

    Identified non-IFN substrate axes: USP18 stabilizes SLC7A11 to limit ferroptosis and recruits MIB2 to drive autophagic GSDMD degradation, antagonizing pyroptosis.

    Evidence Co-IP, ubiquitination assays, site-directed mutagenesis (GSDMD K168), KO/OE, and in vivo inflammation/ferroptosis models

    PMID:38779488 PMID:38959043

    Open questions at the time
    • Whether these are direct catalytic or scaffold-mediated events not fully resolved
    • Single-lab studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • How USP18 is partitioned among its receptor-scaffold, mitochondrial, nuclear, and cytoplasmic functions, and how its weak human catalytic activity is reconciled with the many reported deubiquitination substrates, remains unresolved.
  • No structure of the USP18–IFNAR2–JAK1 assembly
  • Catalytic vs scaffold requirement not dissected for most reported substrates
  • Spatial regulation between compartments unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0016787 hydrolase activity 2
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 2 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 7 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3
Partners
IFNAR2ISG15NEMOSKP2STAT2TAK1TRIM31USP20

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 USP18 (UBP43) specifically removes ISG15 from conjugated proteins via isopeptide bond cleavage; it has no detectable activity toward ubiquitin, SUMO, or NEDD8 in vitro. Deletion of USP18 in mice leads to massive accumulation of ISG15 conjugates, establishing it as the major ISG15-specific protease in vivo. In vitro protease assays with multiple Ubl substrates; ISG15-USP18 fusion self-processing assay; USP18 knockout mouse analysis The Journal of biological chemistry High 11788588
2017 Crystal structures of mouse USP18 alone (open and closed conformations) and in complex with mouse ISG15 revealed that only the C-terminal ubiquitin-like domain of ISG15 is recognized by USP18. A critical hydrophobic patch in USP18 interacts with a hydrophobic region unique to ISG15, providing the molecular basis for ISG15 specificity over ubiquitin. X-ray crystallography of USP18 and USP18–ISG15 complex; biochemical and mutational analysis Nature structural & molecular biology High 28165509
2017 STAT2 recruits USP18 to the type I IFN receptor subunit IFNAR2 via its constitutive membrane-distal STAT2-binding site, acting as an essential adaptor for USP18-mediated negative-feedback suppression of type I IFN signaling in both human and mouse cells. Co-immunoprecipitation, epistasis/rescue experiments, loss-of-function and reconstitution in human and mouse cells Nature structural & molecular biology High 28165510
2011 USP18 induces differential desensitization of the type I IFN system: it is necessary and sufficient to impair formation of functional binding sites for IFN-α2 at the receptor (IFNAR2), while cells primed with either type I or type III IFN retain sensitivity to IFN-β. This defines USP18 as a negative regulator operating at the receptor level. Overexpression and RNAi knockdown of USP18; receptor-binding assays; signaling readouts (STAT phosphorylation, ISG induction) in cell lines PloS one High 21779393
2009 USP18/UBP43 is the key mediator of long-lasting refractoriness of JAK-STAT signaling in mouse liver after repeated IFN-α injections; SOCS1 and SOCS3 are responsible for early termination but not sustained refractoriness, placing USP18 downstream as the dominant negative regulator of prolonged IFN-α signaling in vivo. Repeated in vivo IFN-α injection in mice; genetic epistasis using USP18 KO and SOCS1/SOCS3 KO mice; STAT1 phosphorylation and ISG expression analysis Molecular and cellular biology High 19564419
2015 Knock-in mice expressing enzymatically inactive USP18 (C61A) demonstrate that USP18's inhibition of IFN signaling and prevention of fatal IFN hypersensitivity are independent of its catalytic/isopeptidase activity; however, the isopeptidase activity is required for increased ISGylation and enhanced antiviral resistance to vaccinia and influenza B virus (the latter ISG15-dependently). Catalytic knock-in mouse (USP18-C61A/C61A) compared to USP18 KO; ISG15 KO epistasis; viral challenge assays Proceedings of the National Academy of Sciences of the United States of America High 25605921
2015 USP18 controls microglial quiescence by negatively regulating STAT1 activation and interferon-induced gene expression in a manner independent of its catalytic activity; this function requires interaction with IFNAR2. Absence of IFNAR1 restores microglial activation in USP18-deficient mice, showing that USP18 counters a tonic IFN signal via the IFNAR pathway. Conditional KO of Usp18 in microglia; IFNAR1/IFNAR2 epistasis; STAT1 phosphorylation and ISG expression analyses; catalytically inactive USP18 rescue The EMBO journal High 25896511
2020 USP18 down-regulates type I IFN signaling by sterically blocking JAK1 access to the IFNAR2 subunit of the IFN-I receptor. A patient-derived STAT2 R148Q mutation phenocopies USP18 deficiency because the mutant STAT2 fails to traffic USP18 to IFNAR2, preventing the USP18–IFNAR2 interaction and negative regulation. Patient mutation analysis; functional complementation experiments; signaling assays in patient-derived cells; mechanistic epistasis using STAT2 variants The Journal of experimental medicine High 31940699 32092142
2016 USP18 recruits USP20 to deconjugate K48-linked ubiquitin chains from STING, thereby stabilizing STING and promoting type I IFN and pro-inflammatory cytokine expression after DNA virus (HSV-1) infection. USP18 functions as a scaffold (not as a direct DUB) in this context, facilitating USP20-catalyzed deubiquitination of STING independently of USP18 enzymatic activity. Co-immunoprecipitation; in vitro deubiquitination assay; USP18 and USP20 knockdown/KO; Usp18-/- MEF reconstitution; in vivo HSV-1 infection of Usp18-/- mice Cell research High 27801882
2013 USP18 deubiquitinates the TAK1-TAB1 complex, thereby removing K63-linked polyubiquitin chains from TAK1 and restricting NF-κB and NFAT activation during Th17 differentiation. USP18-deficient T cells exhibit hyperactivation of NF-κB/NFAT and produce excess IL-2, and Usp18-/- mice are resistant to experimental autoimmune encephalomyelitis. Co-immunoprecipitation; in vitro deubiquitination assay; USP18 KO T cells; EAE mouse model; NF-κB/NFAT reporter assays The Journal of experimental medicine High 23825189
2015 USP18 negatively regulates NF-κB signaling by (1) cleaving K63-linked polyubiquitin from TAK1 in a protease-dependent manner, and (2) targeting the IKK complex via direct binding to the UBAN motif of NEMO (IKKγ), specifically inhibiting K63-linked ubiquitination of NEMO through a distinct, protease-independent mechanism. Co-immunoprecipitation; in vitro deubiquitination assay; USP18 knockdown in human macrophages; mutation analysis of UBAN-binding; IKK phosphorylation/IκB degradation assays Scientific reports Medium 26240016
2021 A mitochondria-localized USP18 specifically interacts with MAVS and functions as a scaffold to re-localize TRIM31 to mitochondria, enhancing TRIM31–MAVS interaction and promoting K63-linked polyubiquitination and aggregation of MAVS, thereby upregulating type I IFN after RNA virus infection. This scaffolding activity is independent of USP18 enzymatic activity. Co-immunoprecipitation; ubiquitination assays; USP18-deficient mice with SeV/EMCV infection; subcellular fractionation; TRIM31 re-localization assays Nature communications High 34016972
2006 siRNA knockdown of USP18 in human cells potentiates IFN-α inhibition of HCV RNA replication and infectious virus production, accompanied by increased cellular ISGylation, prolonged STAT1 tyrosine phosphorylation, and enhanced ISG expression, demonstrating that USP18 modulates the anti-HCV type I IFN response. siRNA knockdown; HCV replicon and infectious virus assays; STAT1 phosphorylation assays; ISG expression analysis Gastroenterology Medium 17101330
2011 Human USP18 translation is initiated by a rare CUG start codon, producing a full-length isoform, and also by an internal ribosome entry site (IRES) located in the 5'-coding region, producing an N-terminally truncated isoform (USP18-sf). USP18-sf shows distinct subcellular distribution and enhanced deISGylation activity specifically in the nucleus compared to full-length USP18. Mutagenesis of start codons; IRES reporter assays; subcellular fractionation; in vitro deISGylation assays comparing isoforms The Journal of biological chemistry Medium 22170061
2010 USP18 limits apoptotic susceptibility to IFN-α and bortezomib; its antiapoptotic function is independent of catalytic activity. Ablating USP18 increases TRAIL production, upregulates IRF-1, IRF-7, and IRF-9, and promotes the extrinsic apoptosis pathway, which is abrogated by FLIP overexpression or TRAIL silencing. RNAi screen; overexpression of catalytically inactive USP18 mutant; TRAIL knockdown/FLIP overexpression epistasis; apoptosis assays (Annexin V, caspase) Cancer research Medium 20068173
2017 USP18 protects against hepatic steatosis and insulin resistance by interacting with and deubiquitinating TAK1, thereby inhibiting TAK1 activation and downstream JNK/NF-κB signaling. An active-site mutant USP18 failed to inhibit hepatic steatosis in vivo, demonstrating the requirement for catalytic activity in this metabolic context. Co-immunoprecipitation; in vitro deubiquitination assay; hepatocyte-specific USP18 transgenic and KO mice on HFD; active-site mutant rescue experiments; TAK1 inhibitor epistasis Hepatology (Baltimore, Md.) High 28718215
2019 USP18 interacts with SKP2 (the substrate-recognition subunit of SCF-SKP2 E3 ligase), and free ISG15 disrupts this complex, liberating USP18 from SKP2-mediated proteasomal degradation while concomitantly driving SKP2 to degradation and/or ISGylation. USP18 silencing slows HeLa S3 cell progression toward S phase, linking USP18/ISG15/SKP2 dynamics to cell cycle progression. Co-immunoprecipitation; overexpression/silencing of USP18, ISG15, SKP2; cell cycle analysis (flow cytometry); proteasome inhibitor experiments Scientific reports Medium 30858391
2017 ISG15 directly conjugates to PTEN; USP18 overexpression stabilizes PTEN protein (extending its half-life), while USP18 knockdown destabilizes cytoplasmic PTEN and reduces cytoplasmic PTEN relative to nuclear levels. Immunoprecipitation confirmed ISG15 covalently conjugates to PTEN, and USP18 acts as a novel regulator of PTEN stability via deISGylation. Reverse-phase protein arrays (RPPA); cycloheximide chase; co-immunoprecipitation to detect ISG15-PTEN conjugation; subcellular fractionation; USP18 KD and OE Oncotarget Medium 27980214
2020 Nuclear USP18 controls the enhancer landscape of cancer cells and diminishes STAT2-mediated transcription complex binding to IFN-responsive elements, thereby suppressing canonical ISGs and a set of atypical ISGs/NF-κB targets including PLK2 that induce cancer cell pyroptosis when USP18 is depleted. ChIP-seq / ATAC-seq for enhancer landscape; USP18 KO in cancer cell lines; transcriptomic analysis; functional pyroptosis assays Nature communications Medium 36646704
2022 A partial-loss-of-function USP18 variant (I60N) is normally stabilized by ISG15 and retains deISGylation activity, but interacts poorly with STAT2 and is therefore impaired in negative regulation of IFN-I signaling at IFNAR2. This demonstrates that the STAT2-binding interface is functionally separable from the catalytic domain and from ISG15-mediated stabilization. Patient variant analysis; functional assays in patient cells; co-immunoprecipitation of USP18-I60N vs wild-type with STAT2 and IFNAR2; ISG15 stabilization assays; IFN signaling readouts The Journal of experimental medicine High 35258551
2024 The CRL3-KCTD10 E3 ligase ubiquitylates SLC7A11 for degradation, while USP18 acts as the deubiquitylase that stabilizes SLC7A11. Upon cystine deprivation, USP18 protein levels increase, contributing to SLC7A11 accumulation and reduced ferroptosis. USP18 thus coordinately regulates cystine uptake and ferroptosis through the CRL3-KCTD10/USP18 axis. Co-immunoprecipitation to identify KCTD10 and USP18 interactions with SLC7A11; ubiquitination assays; USP18/KCTD10 KO and OE; cystine uptake assays; ferroptosis assays Proceedings of the National Academy of Sciences of the United States of America Medium 38959043
2021 USP18 binds, deubiquitinates, and stabilizes SOX9, thereby promoting reactive astrogliosis. Hedgehog signaling induces USP18 expression through Gli2-mediated transcriptional activation after spinal cord injury. Conditional USP18 KO in astrocytes attenuates reactive astrogliosis and worsens recovery, while AAV-USP18 overexpression promotes astrogliosis and recovery. Co-immunoprecipitation; ubiquitination assay; astrocyte-conditional KO mouse; AAV-USP18 overexpression mouse; scratch injury in vitro; ChIP for Gli2-USP18 promoter; functional recovery assays Glia Medium 33694203
2020 USP18 deubiquitinates and stabilizes Twist1 by interacting with it and removing its ubiquitination, leading to enhanced EMT in glioblastoma cells. shRNA-mediated USP18 depletion accelerates Twist1 degradation and inhibits GBM invasion/migration in vitro and in vivo; Twist1 reconstitution rescues the inhibitory effects of USP18 depletion. Co-immunoprecipitation; ubiquitination assay; shRNA KD in vitro and in vivo (nude mouse model); Twist1 rescue experiments American journal of cancer research Medium 32368392
2024 USP18 recruits E3 ubiquitin ligase MIB2 to catalyze ubiquitination of GSDMD at lysine 168, which serves as a recognition signal for selective autophagic degradation of GSDMD, thereby negatively regulating pyroptosis. USP18 therefore antagonizes pyroptosis by targeting GSDMD for autophagic (not proteasomal) degradation through this scaffold-like mechanism. Co-immunoprecipitation; site-directed mutagenesis (K168 on GSDMD); ubiquitination assays; autophagy inhibitor experiments; in vivo LPS-induced inflammation model Research (Washington, D.C.) Medium 38779488
2009 Usp18 knockdown reduces EGFR protein expression by 50–80% without changing EGFR mRNA levels; metabolic labeling shows this is due to reduced EGFR protein synthesis (up to 4-fold reduction in translation rate) requiring the native 5' and 3' UTR sequences of EGFR mRNA. Overexpression of Usp18 elevated EGFR levels in a manner requiring the catalytic cysteine. RNAi screen; metabolic radiolabeling; EGFR mRNA and protein assays; Usp18 catalytic mutant overexpression; UTR reporter assays Molecular biology of the cell Medium 19158387
2023 USP18 interacts with and stabilizes FTO protein through deubiquitination, preventing its proteasomal degradation. Stabilized FTO reduces m6A modification of SIRT6 mRNA in a YTHDF2-dependent manner, increasing SIRT6 expression and activating downstream AMPK/PGC-1α/AKT signaling to promote mitophagy and neuroprotection in ischemic stroke models. Co-immunoprecipitation; Western blot for protein stability; RIP and MeRIP (m6A assay); in vitro OGD/R and in vivo MCAO models; USP18/FTO overexpression Molecular neurobiology Medium 38340205
2024 Human USP18 exhibits minimal catalytic (ISG15-cleaving) activity compared to mouse USP18; a patient-derived mutation (I60N) that impairs scaffold function (IFNAR2 binding via STAT2) but not catalytic activity demonstrates that scaffold function is critical for cancer cell vulnerability to type I IFN. These findings resolve the relative importance of catalytic vs. scaffold function in human USP18. Biochemical catalytic activity assays comparing human vs mouse USP18; patient-derived I60N vs catalytic C64S mutant comparison; cellular IFN signaling assays; cancer cell viability readouts iScience High 38632987
2020 USP18 interacts with SKP2 and forms a complex with SAMHD1 in differentiated myeloid THP-1 cells; USP18 downregulates p21 protein expression through this SKP2 interaction, which correlates with elevated intracellular dNTP levels and the antiviral-inactive (T592-phosphorylated) form of SAMHD1, thereby promoting HIV-1 reverse transcription. CRISPR-Cas9 KO of USP18 increases p21 and blocks HIV-1 replication. Co-immunoprecipitation; CRISPR-Cas9 KO; intracellular dNTP assay; SAMHD1 phosphorylation assays; HIV-1 replication assay Journal of virology Medium 30068654
2023 USP18 deubiquitinates and stabilizes Notch1 by removing K48-linked ubiquitin chains, thereby activating the Notch1-c-Myc pathway to promote pancreatic cancer progression. Co-immunoprecipitation; ubiquitination assay showing K48-linked chain removal; in vitro and in vivo (xenograft) functional assays Aging Medium 33051403
2019 ISG15 stabilizes USP18 protein by preventing its SKP2-mediated proteasomal degradation; free ISG15 competes with SKP2 binding to USP18, and USP18 itself stabilizes SKP2 in a reciprocal relationship, placing USP18 as a substrate and regulator of SCF-SKP2 at baseline (non-stimulated) conditions. Co-immunoprecipitation; overexpression/silencing; proteasome inhibitor experiments; cell cycle analysis Scientific reports Medium 30858391
2000 Human USP18 (UBP43) encodes a 372-amino-acid deubiquitinating enzyme with all structural motifs of the USP family; transfection analysis demonstrated that USP18 is a nuclear protein. cDNA cloning; transfection with tagged constructs; subcellular localization by immunofluorescence Genomics Medium 10777664
2019 FOXO3a is ISGylated and subsequently degraded by the proteasome; overexpression of USP18 stabilizes FOXO3a through de-ISGylation, extending its half-life. Overexpression of FOXO3a attenuated TGF-β1-induced fibronectin expression in lung fibroblasts, linking USP18-mediated deISGylation to FOXO3a stability and fibrosis signaling. ISGylation assays (overexpression of ISG15/UBE1L/UBCH8); cycloheximide chase; proteasome/lysosome inhibitor experiments; USP18 overexpression with co-IP; fibronectin expression assay Journal of investigative medicine Medium 31874933
2023 USP18 reduces K48-linked ubiquitination of cGAS and thereby prevents its degradation; stabilized cGAS promotes protective autophagy in vemurafenib-resistant melanoma cells. USP18 thus promotes vemurafenib resistance through cGAS stabilization and autophagic induction. Co-immunoprecipitation; ubiquitination assay; knockdown/overexpression of USP18 and cGAS; xenograft in vivo model International immunopharmacology Medium 37478666
2023 USP18 reduces K48-linked ubiquitination of cGAS, stabilizing cGAS protein in IAV-infected A549 cells, which promotes cGAS-STING pathway activation and innate immune cytokine production as well as apoptosis during influenza A virus infection. Ubiquitination assay (K48-linked); USP18 overexpression/knockdown; cGAS-STING pathway assays; viral titer by plaque assay Virology Medium 37422930
2023 USP18 deubiquitinates and stabilizes ZEB1 in esophageal squamous cell carcinoma cells by directly binding ZEB1 and decreasing its ubiquitination, thereby promoting ZEB1-mediated EMT and tumor metastasis. Co-immunoprecipitation; ubiquitination assay; shRNA KD in vitro and lung metastasis xenograft model in vivo Experimental cell research Medium 34743935
2023 USP18 reprograms tumor-associated macrophages by preventing NEDD4-mediated ubiquitination and degradation of CSF1R; enhanced IFN-I signaling upon USP18 deletion increases ubiquitin E2 (UBE2H5) expression, enabling NEDD4-mediated CSF1R degradation. USP18 impairs NEDD4 binding to CSF1R, thereby stabilizing CSF1R and maintaining tumor-promoting macrophage polarization. Co-immunoprecipitation; ubiquitination assays; USP18 myeloid-specific deletion; in vitro macrophage polarization assays; tumor growth assays Cell reports Medium 38100351

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 UBP43 (USP18) specifically removes ISG15 from conjugated proteins. The Journal of biological chemistry 443 11788588
2011 USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response. PloS one 230 21779393
2004 Role of ISG15 protease UBP43 (USP18) in innate immunity to viral infection. Nature medicine 228 15531891
2015 USP18 lack in microglia causes destructive interferonopathy of the mouse brain. The EMBO journal 180 25896511
2017 STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling. Nature structural & molecular biology 156 28165510
2009 Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43. Molecular and cellular biology 151 19564419
2016 USP18 recruits USP20 to promote innate antiviral response through deubiquitinating STING/MITA. Cell research 143 27801882
2006 Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection. Gastroenterology 141 17101330
2016 Multiple functions of USP18. Cell death & disease 134 27809302
2013 USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex. The Journal of experimental medicine 113 23825189
2017 Structural basis of the specificity of USP18 toward ISG15. Nature structural & molecular biology 107 28165509
2021 USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS. Nature communications 105 34016972
2015 USP18 negatively regulates NF-κB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms. Scientific reports 103 26240016
2015 Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance. Proceedings of the National Academy of Sciences of the United States of America 102 25605921
2020 Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy. The Journal of experimental medicine 90 32092142
2010 Identification of USP18 as an important regulator of the susceptibility to IFN-alpha and drug-induced apoptosis. Cancer research 87 20068173
2020 JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency. The New England journal of medicine 84 31940699
2018 USP18 - a multifunctional component in the interferon response. Bioscience reports 80 30126853
2013 Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λ and elevated secretion of Cxcl10. EMBO molecular medicine 71 23681607
2023 Expansion of interferon inducible gene pool via USP18 inhibition promotes cancer cell pyroptosis. Nature communications 67 36646704
2008 The level of hepatitis B virus replication is not affected by protein ISG15 modification but is reduced by inhibition of UBP43 (USP18) expression. Journal of immunology (Baltimore, Md. : 1950) 67 18941237
2017 USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity. Hepatology (Baltimore, Md.) 65 28718215
2012 USP18 is a key regulator of the interferon-driven gene network modulating pancreatic beta cell inflammation and apoptosis. Cell death & disease 65 23152055
2011 Usp18 regulates epidermal growth factor (EGF) receptor expression and cancer cell survival via microRNA-7. The Journal of biological chemistry 61 21592959
2000 Cloning and characterization of a novel human ubiquitin-specific protease, a homologue of murine UBP43 (Usp18). Genomics 60 10777664
2012 Interferon-γ-stimulated genes, but not USP18, are expressed in livers of patients with acute hepatitis C. Gastroenterology 55 22677194
2022 A partial form of inherited human USP18 deficiency underlies infection and inflammation. The Journal of experimental medicine 54 35258551
2020 Emerging Roles of USP18: From Biology to Pathophysiology. International journal of molecular sciences 53 32957626
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
2021 Dysregulation of USP18/FTO/PYCR1 signaling network promotes bladder cancer development and progression. Aging 51 33461172
2024 The CRL3KCTD10 ubiquitin ligase-USP18 axis coordinately regulates cystine uptake and ferroptosis by modulating SLC7A11. Proceedings of the National Academy of Sciences of the United States of America 49 38959043
2018 USP18 promotes breast cancer growth by upregulating EGFR and activating the AKT/Skp2 pathway. International journal of oncology 48 29749454
2012 USP18 establishes the transcriptional and anti-proliferative interferon α/β differential. The Biochemical journal 48 22731491
2017 The ISG15-specific protease USP18 regulates stability of PTEN. Oncotarget 45 27980214
2020 Strategies to Target ISG15 and USP18 Toward Therapeutic Applications. Frontiers in chemistry 44 32039148
2023 LncRNA BCCE4 Genetically Enhances the PD-L1/PD-1 Interaction in Smoking-Related Bladder Cancer by Modulating miR-328-3p-USP18 Signaling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 43 37705121
2018 Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target. Cancer research 43 29343520
2016 Acetaldehyde Disrupts Interferon Alpha Signaling in Hepatitis C Virus-Infected Liver Cells by Up-Regulating USP18. Alcoholism, clinical and experimental research 43 27716962
2020 The Ubiquitin-Specific Peptidase USP18 Promotes Lipolysis, Fatty Acid Oxidation, and Lung Cancer Growth. Molecular cancer research : MCR 42 33380466
2018 CRISPR/Cas9 knockout of USP18 enhances type I IFN responsiveness and restricts HIV-1 infection in macrophages. Journal of leukocyte biology 42 29437254
2014 USP18 is crucial for IFN-γ-mediated inhibition of B16 melanoma tumorigenesis and antitumor immunity. Molecular cancer 42 24884733
2020 Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity. British journal of cancer 41 33214684
2014 Contribution of increased ISG15, ISGylation and deregulated type I IFN signaling in Usp18 mutant mice during the course of bacterial infections. Genes and immunity 39 24807690
2009 RNA interference screen identifies Usp18 as a regulator of epidermal growth factor receptor synthesis. Molecular biology of the cell 39 19158387
2017 Deubiquitinase USP18 Loss Mislocalizes and Destabilizes KRAS in Lung Cancer. Molecular cancer research : MCR 38 28242811
2020 USP18 promotes cell proliferation and suppressed apoptosis in cervical cancer cells via activating AKT signaling pathway. BMC cancer 37 32770981
2011 Two independent mechanisms promote expression of an N-terminal truncated USP18 isoform with higher DeISGylation activity in the nucleus. The Journal of biological chemistry 36 22170061
2020 USP18 deubiquitinates and stabilizes Twist1 to promote epithelial-mesenchymal transition in glioblastoma cells. American journal of cancer research 35 32368392
2019 USP18 and ISG15 coordinately impact on SKP2 and cell cycle progression. Scientific reports 35 30858391
2016 Suppression of USP18 Potentiates the Anti-HBV Activity of Interferon Alpha in HepG2.2.15 Cells via JAK/STAT Signaling. PloS one 35 27227879
2020 USP18 directly regulates Snail1 protein through ubiquitination pathway in colorectal cancer. Cancer cell international 34 32742193
2021 Deubiquitinase USP18 regulates reactive astrogliosis by stabilizing SOX9. Glia 31 33694203
2024 USP18 Stabilized FTO Protein to Activate Mitophagy in Ischemic Stroke Through Repressing m6A Modification of SIRT6. Molecular neurobiology 30 38340205
2020 Deubiquitinase USP18 promotes the progression of pancreatic cancer via enhancing the Notch1-c-Myc axis. Aging 30 33051403
2018 USP18 (UBP43) Abrogates p21-Mediated Inhibition of HIV-1. Journal of virology 30 30068654
2016 Lipopolysaccharide and Tumor Necrosis Factor Alpha Inhibit Interferon Signaling in Hepatocytes by Increasing Ubiquitin-Like Protease 18 (USP18) Expression. Journal of virology 30 27009955
2014 Novel combination markers for predicting survival in patients with muscle invasive bladder cancer: USP18 and DGCR2. Journal of Korean medical science 30 24616583
2013 Roles of the ubiquitin peptidase USP18 in multiple sclerosis and the response to interferon-β treatment. European journal of neurology 30 23700969
2021 USP18 mitigates lipopolysaccharide-induced oxidative stress and inflammation in human pulmonary microvascular endothelial cells through the TLR4/NF-κB/ROS signaling. Toxicology in vitro : an international journal published in association with BIBRA 29 33930521
2016 Elevated Response to Type I IFN Enhances RANKL-Mediated Osteoclastogenesis in Usp18-Knockout Mice. Journal of immunology (Baltimore, Md. : 1950) 29 27016605
2019 USP18 Overexpression Protects against Focal Cerebral Ischemia Injury in Mice by Suppressing Microglial Activation. Neuroscience 25 31513843
2017 IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection. Scientific reports 25 28630501
2023 ISG15-USP18 Dysregulation by Oxidative Stress Promotes IFN-γ Secretion from CD8+ T Cells in Vitiligo. The Journal of investigative dermatology 24 37625543
2021 USP18 promotes tumor metastasis in esophageal squamous cell carcinomas via deubiquitinating ZEB1. Experimental cell research 24 34743935
2012 USP18 restricts PRRSV growth through alteration of nuclear translocation of NF-κB p65 and p50 in MARC-145 cells. Virus research 24 22796444
2021 USP18 Mediates Interferon Resistance of Dengue Virus Infection. Frontiers in microbiology 23 34017322
2018 The probacterial effect of type I interferon signaling requires its own negative regulator USP18. Science immunology 23 30266866
2017 Downregulation of USP18 inhibits growth and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma cells by suppressing BCL2L1. Experimental cell research 23 28709980
2012 Usp18 promotes conventional CD11b+ dendritic cell development. Journal of immunology (Baltimore, Md. : 1950) 23 22491252
2024 USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D. Research (Washington, D.C.) 22 38779488
2023 Reprogramming of tumor-associated macrophages via NEDD4-mediated CSF1R degradation by targeting USP18. Cell reports 21 38100351
2017 How USP18 deals with ISG15-modified proteins: structural basis for the specificity of the protease. The FEBS journal 21 28881486
2013 Ubiquitin specific protease 18 (Usp18) is a WT1 transcriptional target. Experimental cell research 20 23291318
2016 IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18. The Journal of general virology 19 27302182
2012 High yield expression of catalytically active USP18 (UBP43) using a Trigger Factor fusion system. BMC biotechnology 18 22916876
2024 ISG15/USP18/STAT2 is a molecular hub regulating IFN I-mediated control of Dengue and Zika virus replication. Frontiers in immunology 17 38384473
2023 Taxifolin inhibits melanoma proliferation/migration impeding USP18/Rac1/JNK/β-catenin oncogenic signaling. Phytomedicine : international journal of phytotherapy and phytopharmacology 17 37995531
2017 Deubiquitinase Usp18 prevents cellular apoptosis from oxidative stress in liver cells. Cell biology international 17 28557172
2015 Mice null for the deubiquitinase USP18 spontaneously develop leiomyosarcomas. BMC cancer 16 26555296
2023 USP18 is an essential regulator of muscle cell differentiation and maturation. Cell death & disease 15 37002195
2019 Expression of USP18 and IL2RA Is Increased in Individuals Receiving Latent Tuberculosis Treatment with Isoniazid. Journal of immunology research 15 31886294
2013 The DeISGylase USP18 limits TRAIL-induced apoptosis through the regulation of TRAIL levels: Cellular levels of TRAIL influences responsiveness to TRAIL-induced apoptosis. Cancer biology & therapy 15 24153058
2015 ISG15 uncut: Dissecting enzymatic and non-enzymatic functions of USP18 in vivo. Cytokine 14 25805508
2023 USP18 promotes endometrial receptivity via the JAK/STAT1 and the ISGylation pathway. Theriogenology 13 36934584
2022 USP18 reduces paclitaxol sensitivity of triple-negative breast cancer via autophagy. Biochemical and biophysical research communications 13 35180471
2019 USP18 is a significant driver of memory CD4 T-cell reduced viability caused by type I IFN signaling during primary HIV-1 infection. PLoS pathogens 13 31658294
2024 Type I interferon regulation by USP18 is a key vulnerability in cancer. iScience 12 38632987
2024 USP18 induction regulates immunometabolism to attenuate M1 signal-polarized macrophages and enhance IL-4-polarized macrophages in systemic lupus erythematosus. Clinical immunology (Orlando, Fla.) 12 38880201
2024 Mechanism of USP18-Mediated NCOA4 m6A Modification Via Maintaining FTO Stability In Regulating Ferritinophagy-Mediated Ferroptosis in Cerebral Ischemia-Reperfusion Injury. Molecular neurobiology 12 39331352
2023 USP18 promotes innate immune responses and apoptosis in influenza A virus-infected A549 cells via cGAS-STING pathway. Virology 12 37422930
2023 USP18 enhances dengue virus replication by regulating mitochondrial DNA release. Scientific reports 12 37978268
2021 USP18 and USP20 restrict oHSV-1 replication in resistant human oral squamous carcinoma cell line SCC9 and affect the viability of SCC9 cells. Molecular therapy oncolytics 12 34901390
2009 Functional analysis of the porcine USP18 and its role during porcine arterivirus replication. Gene 12 19285125
2023 USP18 overexpression protects against spinal cord ischemia/reperfusion injury via regulating autophagy. Neuroscience letters 11 37356565
2023 USP18 enhances the resistance of BRAF-mutated melanoma cells to vemurafenib by stabilizing cGAS expression to induce cell autophagy. International immunopharmacology 11 37478666
2021 People with HIV-1 demonstrate type 1 interferon refractoriness associated with upregulated USP18. Journal of virology 11 33658340
2011 Knockdown of USP18 increases α 2a interferon signaling and induction of interferon-stimulating genes but does not increase antiviral activity in Huh7 cells. Antimicrobial agents and chemotherapy 11 21709085
2022 The USP18-FBXO6 axis maintains the malignancy of ovarian cancer. Biochemical and biophysical research communications 10 35063764
2019 Versatility of USP18 in physiology and pathophysiology. Acta biochimica Polonica 10 31747454
2019 FOXO3a is stabilized by USP18-mediated de-ISGylation and inhibits TGF-β1-induced fibronectin expression. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 10 31874933

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