{"gene":"USP18","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"In vitro protease assays with multiple Ubl substrates; ISG15-USP18 fusion self-processing assay; USP18 knockout mouse analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with multiple substrates, mutagenesis-based self-processing assay, and replicated in vivo KO model; foundational paper replicated across many subsequent studies","pmids":["11788588"],"is_preprint":false},{"year":2017,"finding":"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.","method":"X-ray crystallography of USP18 and USP18–ISG15 complex; biochemical and mutational analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis validation in a single rigorous study; multiple orthogonal methods","pmids":["28165509"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, epistasis/rescue experiments, loss-of-function and reconstitution in human and mouse cells","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional reconstitution, replicated in two species with multiple orthogonal methods","pmids":["28165510"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Overexpression and RNAi knockdown of USP18; receptor-binding assays; signaling readouts (STAT phosphorylation, ISG induction) in cell lines","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with receptor-level mechanistic readout, multiple orthogonal assays, single lab","pmids":["21779393"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Repeated in vivo IFN-α injection in mice; genetic epistasis using USP18 KO and SOCS1/SOCS3 KO mice; STAT1 phosphorylation and ISG expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with multiple KO models and multiple signaling readouts; clearly places USP18 in pathway","pmids":["19564419"],"is_preprint":false},{"year":2015,"finding":"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).","method":"Catalytic knock-in mouse (USP18-C61A/C61A) compared to USP18 KO; ISG15 KO epistasis; viral challenge assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo active-site mutagenesis (knock-in) with epistasis analysis across multiple KO backgrounds; directly dissects enzymatic vs non-enzymatic functions","pmids":["25605921"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Conditional KO of Usp18 in microglia; IFNAR1/IFNAR2 epistasis; STAT1 phosphorylation and ISG expression analyses; catalytically inactive USP18 rescue","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with IFNAR epistasis and catalytic-activity dissection; multiple orthogonal methods; published in high-impact journal","pmids":["25896511"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Patient mutation analysis; functional complementation experiments; signaling assays in patient-derived cells; mechanistic epistasis using STAT2 variants","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — human patient mutation combined with functional cellular reconstitution across two independent studies (PMID 28165510 and 31940699 corroborate the JAK1-blocking mechanism)","pmids":["32092142","31940699"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation; in vitro deubiquitination assay; USP18 and USP20 knockdown/KO; Usp18-/- MEF reconstitution; in vivo HSV-1 infection of Usp18-/- mice","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro DUB assay showing USP18 alone cannot deubiquitinate STING, KO rescue, and in vivo validation; multiple orthogonal methods","pmids":["27801882"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation; in vitro deubiquitination assay; USP18 KO T cells; EAE mouse model; NF-κB/NFAT reporter assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus in vitro deubiquitination assay plus in vivo KO phenotype; multiple orthogonal methods in one study","pmids":["23825189"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation; in vitro deubiquitination assay; USP18 knockdown in human macrophages; mutation analysis of UBAN-binding; IKK phosphorylation/IκB degradation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro DUB assay plus mutation analysis, single lab","pmids":["26240016"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation; ubiquitination assays; USP18-deficient mice with SeV/EMCV infection; subcellular fractionation; TRIM31 re-localization assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, subcellular localization with functional consequence, in vivo KO model, multiple orthogonal methods","pmids":["34016972"],"is_preprint":false},{"year":2006,"finding":"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.","method":"siRNA knockdown; HCV replicon and infectious virus assays; STAT1 phosphorylation assays; ISG expression analysis","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple pathway readouts, single lab","pmids":["17101330"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Mutagenesis of start codons; IRES reporter assays; subcellular fractionation; in vitro deISGylation assays comparing isoforms","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus functional assays plus fractionation, single lab, single study","pmids":["22170061"],"is_preprint":false},{"year":2010,"finding":"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.","method":"RNAi screen; overexpression of catalytically inactive USP18 mutant; TRAIL knockdown/FLIP overexpression epistasis; apoptosis assays (Annexin V, caspase)","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant rescue dissects enzymatic vs non-enzymatic function; epistasis with TRAIL/FLIP; single lab","pmids":["20068173"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation; in vitro deubiquitination assay; hepatocyte-specific USP18 transgenic and KO mice on HFD; active-site mutant rescue experiments; TAK1 inhibitor epistasis","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro deubiquitination assay, active-site mutagenesis in vivo, hepatocyte-specific genetic models, epistasis with TAK1 inhibitor; multiple orthogonal methods","pmids":["28718215"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation; overexpression/silencing of USP18, ISG15, SKP2; cell cycle analysis (flow cytometry); proteasome inhibitor experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional cell cycle readout, single lab, multiple methods","pmids":["30858391"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Reverse-phase protein arrays (RPPA); cycloheximide chase; co-immunoprecipitation to detect ISG15-PTEN conjugation; subcellular fractionation; USP18 KD and OE","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CHX chase plus Co-IP for ISGylation plus fractionation; single lab, multiple methods","pmids":["27980214"],"is_preprint":false},{"year":2020,"finding":"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.","method":"ChIP-seq / ATAC-seq for enhancer landscape; USP18 KO in cancer cell lines; transcriptomic analysis; functional pyroptosis assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin accessibility plus ChIP data plus KO functional assays; single lab but multiple orthogonal genomic and cellular methods","pmids":["36646704"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived variant with biochemical domain separation (catalytic vs scaffold), Co-IP, and functional signaling assays; multiple orthogonal methods","pmids":["35258551"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation to identify KCTD10 and USP18 interactions with SLC7A11; ubiquitination assays; USP18/KCTD10 KO and OE; cystine uptake assays; ferroptosis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional KO/OE; single lab, multiple methods","pmids":["38959043"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation; ubiquitination assay; astrocyte-conditional KO mouse; AAV-USP18 overexpression mouse; scratch injury in vitro; ChIP for Gli2-USP18 promoter; functional recovery assays","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus conditional KO in vivo; single lab, multiple orthogonal methods","pmids":["33694203"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation; ubiquitination assay; shRNA KD in vitro and in vivo (nude mouse model); Twist1 rescue experiments","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo rescue; single lab","pmids":["32368392"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation; site-directed mutagenesis (K168 on GSDMD); ubiquitination assays; autophagy inhibitor experiments; in vivo LPS-induced inflammation model","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis identifying specific ubiquitination site plus functional assays; single lab","pmids":["38779488"],"is_preprint":false},{"year":2009,"finding":"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.","method":"RNAi screen; metabolic radiolabeling; EGFR mRNA and protein assays; Usp18 catalytic mutant overexpression; UTR reporter assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant dissection plus metabolic labeling plus UTR assays; single lab, multiple orthogonal methods","pmids":["19158387"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation; Western blot for protein stability; RIP and MeRIP (m6A assay); in vitro OGD/R and in vivo MCAO models; USP18/FTO overexpression","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus m6A assay plus epistasis; single lab, multiple methods","pmids":["38340205"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay plus mutagenesis of both catalytic and scaffold functions with cellular validation; single lab but multiple orthogonal methods","pmids":["38632987"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation; CRISPR-Cas9 KO; intracellular dNTP assay; SAMHD1 phosphorylation assays; HIV-1 replication assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus CRISPR KO plus dNTP/SAMHD1 mechanistic readouts; single lab","pmids":["30068654"],"is_preprint":false},{"year":2023,"finding":"USP18 deubiquitinates and stabilizes Notch1 by removing K48-linked ubiquitin chains, thereby activating the Notch1-c-Myc pathway to promote pancreatic cancer progression.","method":"Co-immunoprecipitation; ubiquitination assay showing K48-linked chain removal; in vitro and in vivo (xenograft) functional assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro ubiquitination assay plus in vivo rescue; single lab","pmids":["33051403"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation; overexpression/silencing; proteasome inhibitor experiments; cell cycle analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional proteasome inhibitor rescue plus cell cycle readout; single lab","pmids":["30858391"],"is_preprint":false},{"year":2000,"finding":"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.","method":"cDNA cloning; transfection with tagged constructs; subcellular localization by immunofluorescence","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment; single method but replicated in subsequent studies showing nuclear localization of a truncated isoform","pmids":["10777664"],"is_preprint":false},{"year":2019,"finding":"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.","method":"ISGylation assays (overexpression of ISG15/UBE1L/UBCH8); cycloheximide chase; proteasome/lysosome inhibitor experiments; USP18 overexpression with co-IP; fibronectin expression assay","journal":"Journal of investigative medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CHX chase plus ISGylation assay plus proteasome inhibitor; single lab","pmids":["31874933"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation; ubiquitination assay; knockdown/overexpression of USP18 and cGAS; xenograft in vivo model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo validation; single lab","pmids":["37478666"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Ubiquitination assay (K48-linked); USP18 overexpression/knockdown; cGAS-STING pathway assays; viral titer by plaque assay","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay plus functional pathway assays; single lab","pmids":["37422930"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation; ubiquitination assay; shRNA KD in vitro and lung metastasis xenograft model in vivo","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo xenograft; single lab","pmids":["34743935"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation; ubiquitination assays; USP18 myeloid-specific deletion; in vitro macrophage polarization assays; tumor growth assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus myeloid-conditional KO; single lab, multiple methods","pmids":["38100351"],"is_preprint":false}],"current_model":"USP18 is a bifunctional protein that (1) specifically cleaves ISG15 from ISGylated substrates via its catalytic cysteine (with minimal activity toward ubiquitin, particularly in humans), and (2) acts as a scaffold that, when recruited to IFNAR2 by STAT2, sterically blocks JAK1 access to the receptor and thereby negatively regulates type I IFN signaling independently of its catalytic activity; additionally, it deubiquitinates multiple substrates (TAK1, NEMO, STING via USP20 recruitment, MAVS-related TRIM31 scaffolding, Notch1, Twist1, ZEB1, SOX9, FTO, cGAS, SLC7A11, KRAS, PTEN, FOXO3a) to modulate NF-κB, antiviral, metabolic, and oncogenic pathways, while its own stability is controlled by ISG15-mediated protection from SKP2-dependent proteasomal degradation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2000,"claim":"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","pmids":["10777664"],"confidence":"Medium","gaps":["Did not define substrate specificity","Did not address non-nuclear isoforms or functions"]},{"year":2002,"claim":"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","pmids":["11788588"],"confidence":"High","gaps":["Did not explain the structural basis for ISG15 over ubiquitin selectivity","Did not address non-catalytic functions"]},{"year":2006,"claim":"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","pmids":["17101330"],"confidence":"Medium","gaps":["Did not separate ISGylation effects from receptor-level signaling effects","Single-lab loss-of-function"]},{"year":2009,"claim":"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","pmids":["19564419"],"confidence":"High","gaps":["Did not define the molecular mechanism at the receptor","Did not establish whether catalytic activity is required"]},{"year":2011,"claim":"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","pmids":["21779393"],"confidence":"High","gaps":["Did not identify the adaptor recruiting USP18 to the receptor","Did not resolve catalytic requirement"]},{"year":2011,"claim":"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","pmids":["22170061"],"confidence":"Medium","gaps":["Physiological role of the short isoform not established in vivo","Single-study observation"]},{"year":2015,"claim":"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","pmids":["25605921"],"confidence":"High","gaps":["Did not define the scaffold molecular mechanism","Did not map the protein interface used for non-catalytic function"]},{"year":2015,"claim":"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","pmids":["25896511"],"confidence":"High","gaps":["Did not define the receptor-proximal molecular block","Source of tonic IFN not identified"]},{"year":2013,"claim":"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","pmids":["23825189"],"confidence":"High","gaps":["Did not address whether scaffold or catalytic mechanism dominates in other cell types"]},{"year":2015,"claim":"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","pmids":["26240016"],"confidence":"Medium","gaps":["NEMO interface not structurally defined","Single-lab study"]},{"year":2016,"claim":"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","pmids":["27801882"],"confidence":"High","gaps":["Did not define how USP18 selects USP20 over other DUBs","Structural basis of the ternary complex unknown"]},{"year":2017,"claim":"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","pmids":["28165509"],"confidence":"High","gaps":["Structures are of mouse protein; human catalytic weakness not yet structurally explained","Did not capture the STAT2/IFNAR2 scaffold interface"]},{"year":2017,"claim":"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","pmids":["28165510"],"confidence":"High","gaps":["Did not yet show the JAK1-blocking step directly","STAT2-binding interface on USP18 not mapped"]},{"year":2017,"claim":"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","pmids":["27980214"],"confidence":"Medium","gaps":["In vivo relevance not established","Single-lab study"]},{"year":2017,"claim":"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","pmids":["28718215"],"confidence":"High","gaps":["Did not reconcile catalytic requirement here with catalysis-independent TAK1/NEMO mechanisms reported elsewhere"]},{"year":2019,"claim":"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","pmids":["30858391"],"confidence":"Medium","gaps":["Direct cell-cycle substrate of USP18 not identified","Single-lab study"]},{"year":2019,"claim":"Added FOXO3a as a deISGylation target, linking USP18 to fibrosis signaling.","evidence":"ISGylation assays, CHX chase, proteasome inhibition, and fibronectin readout in lung fibroblasts","pmids":["31874933"],"confidence":"Medium","gaps":["In vivo fibrosis role not tested","Single-lab study"]},{"year":2020,"claim":"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","pmids":["32092142","31940699"],"confidence":"High","gaps":["Atomic structure of the USP18–IFNAR2–JAK1 arrangement not resolved"]},{"year":2020,"claim":"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","pmids":["36646704"],"confidence":"Medium","gaps":["Mechanism connecting nuclear USP18 to chromatin not defined","Single-lab study"]},{"year":2020,"claim":"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","pmids":["30068654"],"confidence":"Medium","gaps":["Direct biochemical link between USP18 and p21 turnover not established","Single-lab study"]},{"year":2021,"claim":"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","pmids":["34016972"],"confidence":"High","gaps":["How USP18 partitions between receptor, mitochondria, and nucleus not resolved"]},{"year":2021,"claim":"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","pmids":["33694203"],"confidence":"Medium","gaps":["Catalytic vs scaffold requirement for SOX9 stabilization not dissected","Single-lab study"]},{"year":2022,"claim":"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","pmids":["35258551"],"confidence":"High","gaps":["Atomic mapping of the STAT2-binding surface not provided"]},{"year":2023,"claim":"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","pmids":["33051403","34743935","37478666","37422930"],"confidence":"Medium","gaps":["Catalytic vs scaffold mechanism not consistently dissected across substrates","Each link rests on single-lab studies"]},{"year":2023,"claim":"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","pmids":["38340205"],"confidence":"Medium","gaps":["Direct deubiquitination biochemistry on FTO limited","Single-lab study"]},{"year":2024,"claim":"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","pmids":["38632987"],"confidence":"High","gaps":["Structural explanation for weak human catalysis not provided"]},{"year":2024,"claim":"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","pmids":["38959043","38779488"],"confidence":"Medium","gaps":["Whether these are direct catalytic or scaffold-mediated events not fully resolved","Single-lab studies"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,9,15,28,34]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,8,11,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[30,13,18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,7]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,4,7,9,8,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,29,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14,23,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[22,28,34,32]}],"complexes":[],"partners":["STAT2","IFNAR2","USP20","TAK1","NEMO","SKP2","TRIM31","ISG15"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UMW8","full_name":"Ubl carboxyl-terminal hydrolase 18","aliases":["43 kDa ISG15-specific protease","hUBP43","ISG15-specific-processing protease","Ubl thioesterase 18"],"length_aa":372,"mass_kda":43.0,"function":"Interferon-induced ISG15-specific protease that plays a crucial role for maintaining a proper balance of ISG15-conjugated proteins in cells (PubMed:11788588). Regulates protein ISGylation by efficiently cleaving ISG15 conjugates linked via isopeptide bonds. Regulates T-cell activation and T-helper 17 (Th17) cell differentiation by deubiquitinating TAK1, likely to keep TAK1-TAB complexes in steady conditions (PubMed:23825189). In turn, restricts activation of NF-kappa-B, NFAT, and JNK as well as expression of IL2 in T-cells after TCR activation (PubMed:23825189). Acts as a molecular adapter with USP20 to promote innate antiviral response through deubiquitinating STING1 (PubMed:27801882). Involved also in the negative regulation of the inflammatory response triggered by type I interferon (PubMed:27325888, PubMed:28165510). Upon recruitment by STAT2 to the type I interferon receptor subunit IFNAR2 interferes with the assembly of the ternary interferon-IFNAR1-IFNAR2 complex and acts as a negative regulator of the type I interferon signaling pathway (PubMed:28165510) Has enzymatic activity similar to isoform 1 and interferes with type I interferon signaling. Major deISGylation enzyme for nuclear proteins (PubMed:22170061)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UMW8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/USP18","classification":"Common Essential","n_dependent_lines":417,"n_total_lines":1208,"dependency_fraction":0.34519867549668876},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/USP18","total_profiled":1310},"omim":[{"mim_id":"618886","title":"PSEUDO-TORCH SYNDROME 3; PTORCH3","url":"https://www.omim.org/entry/618886"},{"mim_id":"617397","title":"PSEUDO-TORCH SYNDROME 2; PTORCH2","url":"https://www.omim.org/entry/617397"},{"mim_id":"607057","title":"UBIQUITIN-SPECIFIC PROTEASE 18; USP18","url":"https://www.omim.org/entry/607057"},{"mim_id":"600556","title":"SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2; STAT2","url":"https://www.omim.org/entry/600556"},{"mim_id":"251290","title":"PSEUDO-TORCH SYNDROME 1; PTORCH1","url":"https://www.omim.org/entry/251290"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/USP18"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9UMW8","domains":[{"cath_id":"3.90.70.10","chopping":"53-288_297-370","consensus_level":"medium","plddt":93.4274,"start":53,"end":370}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMW8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UMW8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UMW8-F1-predicted_aligned_error_v6.png","plddt_mean":83.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP18","jax_strain_url":"https://www.jax.org/strain/search?query=USP18"},"sequence":{"accession":"Q9UMW8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UMW8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UMW8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMW8"}},"corpus_meta":[{"pmid":"11788588","id":"PMC_11788588","title":"UBP43 (USP18) specifically 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  \"finding\": \"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.\",\n      \"method\": \"In vitro protease assays with multiple Ubl substrates; ISG15-USP18 fusion self-processing assay; USP18 knockout mouse analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with multiple substrates, mutagenesis-based self-processing assay, and replicated in vivo KO model; foundational paper replicated across many subsequent studies\",\n      \"pmids\": [\"11788588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography of USP18 and USP18–ISG15 complex; biochemical and mutational analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis validation in a single rigorous study; multiple orthogonal methods\",\n      \"pmids\": [\"28165509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, epistasis/rescue experiments, loss-of-function and reconstitution in human and mouse cells\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional reconstitution, replicated in two species with multiple orthogonal methods\",\n      \"pmids\": [\"28165510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression and RNAi knockdown of USP18; receptor-binding assays; signaling readouts (STAT phosphorylation, ISG induction) in cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with receptor-level mechanistic readout, multiple orthogonal assays, single lab\",\n      \"pmids\": [\"21779393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Repeated in vivo IFN-α injection in mice; genetic epistasis using USP18 KO and SOCS1/SOCS3 KO mice; STAT1 phosphorylation and ISG expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with multiple KO models and multiple signaling readouts; clearly places USP18 in pathway\",\n      \"pmids\": [\"19564419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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).\",\n      \"method\": \"Catalytic knock-in mouse (USP18-C61A/C61A) compared to USP18 KO; ISG15 KO epistasis; viral challenge assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo active-site mutagenesis (knock-in) with epistasis analysis across multiple KO backgrounds; directly dissects enzymatic vs non-enzymatic functions\",\n      \"pmids\": [\"25605921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional KO of Usp18 in microglia; IFNAR1/IFNAR2 epistasis; STAT1 phosphorylation and ISG expression analyses; catalytically inactive USP18 rescue\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with IFNAR epistasis and catalytic-activity dissection; multiple orthogonal methods; published in high-impact journal\",\n      \"pmids\": [\"25896511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Patient mutation analysis; functional complementation experiments; signaling assays in patient-derived cells; mechanistic epistasis using STAT2 variants\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human patient mutation combined with functional cellular reconstitution across two independent studies (PMID 28165510 and 31940699 corroborate the JAK1-blocking mechanism)\",\n      \"pmids\": [\"32092142\", \"31940699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; in vitro deubiquitination assay; USP18 and USP20 knockdown/KO; Usp18-/- MEF reconstitution; in vivo HSV-1 infection of Usp18-/- mice\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro DUB assay showing USP18 alone cannot deubiquitinate STING, KO rescue, and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"27801882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; in vitro deubiquitination assay; USP18 KO T cells; EAE mouse model; NF-κB/NFAT reporter assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus in vitro deubiquitination assay plus in vivo KO phenotype; multiple orthogonal methods in one study\",\n      \"pmids\": [\"23825189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; in vitro deubiquitination assay; USP18 knockdown in human macrophages; mutation analysis of UBAN-binding; IKK phosphorylation/IκB degradation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro DUB assay plus mutation analysis, single lab\",\n      \"pmids\": [\"26240016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assays; USP18-deficient mice with SeV/EMCV infection; subcellular fractionation; TRIM31 re-localization assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, subcellular localization with functional consequence, in vivo KO model, multiple orthogonal methods\",\n      \"pmids\": [\"34016972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown; HCV replicon and infectious virus assays; STAT1 phosphorylation assays; ISG expression analysis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple pathway readouts, single lab\",\n      \"pmids\": [\"17101330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Mutagenesis of start codons; IRES reporter assays; subcellular fractionation; in vitro deISGylation assays comparing isoforms\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus functional assays plus fractionation, single lab, single study\",\n      \"pmids\": [\"22170061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi screen; overexpression of catalytically inactive USP18 mutant; TRAIL knockdown/FLIP overexpression epistasis; apoptosis assays (Annexin V, caspase)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant rescue dissects enzymatic vs non-enzymatic function; epistasis with TRAIL/FLIP; single lab\",\n      \"pmids\": [\"20068173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; in vitro deubiquitination assay; hepatocyte-specific USP18 transgenic and KO mice on HFD; active-site mutant rescue experiments; TAK1 inhibitor epistasis\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro deubiquitination assay, active-site mutagenesis in vivo, hepatocyte-specific genetic models, epistasis with TAK1 inhibitor; multiple orthogonal methods\",\n      \"pmids\": [\"28718215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; overexpression/silencing of USP18, ISG15, SKP2; cell cycle analysis (flow cytometry); proteasome inhibitor experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional cell cycle readout, single lab, multiple methods\",\n      \"pmids\": [\"30858391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Reverse-phase protein arrays (RPPA); cycloheximide chase; co-immunoprecipitation to detect ISG15-PTEN conjugation; subcellular fractionation; USP18 KD and OE\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CHX chase plus Co-IP for ISGylation plus fractionation; single lab, multiple methods\",\n      \"pmids\": [\"27980214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq / ATAC-seq for enhancer landscape; USP18 KO in cancer cell lines; transcriptomic analysis; functional pyroptosis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin accessibility plus ChIP data plus KO functional assays; single lab but multiple orthogonal genomic and cellular methods\",\n      \"pmids\": [\"36646704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived variant with biochemical domain separation (catalytic vs scaffold), Co-IP, and functional signaling assays; multiple orthogonal methods\",\n      \"pmids\": [\"35258551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation to identify KCTD10 and USP18 interactions with SLC7A11; ubiquitination assays; USP18/KCTD10 KO and OE; cystine uptake assays; ferroptosis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional KO/OE; single lab, multiple methods\",\n      \"pmids\": [\"38959043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; astrocyte-conditional KO mouse; AAV-USP18 overexpression mouse; scratch injury in vitro; ChIP for Gli2-USP18 promoter; functional recovery assays\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus conditional KO in vivo; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33694203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; shRNA KD in vitro and in vivo (nude mouse model); Twist1 rescue experiments\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo rescue; single lab\",\n      \"pmids\": [\"32368392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis (K168 on GSDMD); ubiquitination assays; autophagy inhibitor experiments; in vivo LPS-induced inflammation model\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis identifying specific ubiquitination site plus functional assays; single lab\",\n      \"pmids\": [\"38779488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi screen; metabolic radiolabeling; EGFR mRNA and protein assays; Usp18 catalytic mutant overexpression; UTR reporter assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant dissection plus metabolic labeling plus UTR assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19158387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; Western blot for protein stability; RIP and MeRIP (m6A assay); in vitro OGD/R and in vivo MCAO models; USP18/FTO overexpression\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus m6A assay plus epistasis; single lab, multiple methods\",\n      \"pmids\": [\"38340205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay plus mutagenesis of both catalytic and scaffold functions with cellular validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38632987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; CRISPR-Cas9 KO; intracellular dNTP assay; SAMHD1 phosphorylation assays; HIV-1 replication assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus CRISPR KO plus dNTP/SAMHD1 mechanistic readouts; single lab\",\n      \"pmids\": [\"30068654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP18 deubiquitinates and stabilizes Notch1 by removing K48-linked ubiquitin chains, thereby activating the Notch1-c-Myc pathway to promote pancreatic cancer progression.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay showing K48-linked chain removal; in vitro and in vivo (xenograft) functional assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro ubiquitination assay plus in vivo rescue; single lab\",\n      \"pmids\": [\"33051403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; overexpression/silencing; proteasome inhibitor experiments; cell cycle analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional proteasome inhibitor rescue plus cell cycle readout; single lab\",\n      \"pmids\": [\"30858391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA cloning; transfection with tagged constructs; subcellular localization by immunofluorescence\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment; single method but replicated in subsequent studies showing nuclear localization of a truncated isoform\",\n      \"pmids\": [\"10777664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"ISGylation assays (overexpression of ISG15/UBE1L/UBCH8); cycloheximide chase; proteasome/lysosome inhibitor experiments; USP18 overexpression with co-IP; fibronectin expression assay\",\n      \"journal\": \"Journal of investigative medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CHX chase plus ISGylation assay plus proteasome inhibitor; single lab\",\n      \"pmids\": [\"31874933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; knockdown/overexpression of USP18 and cGAS; xenograft in vivo model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo validation; single lab\",\n      \"pmids\": [\"37478666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Ubiquitination assay (K48-linked); USP18 overexpression/knockdown; cGAS-STING pathway assays; viral titer by plaque assay\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay plus functional pathway assays; single lab\",\n      \"pmids\": [\"37422930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; shRNA KD in vitro and lung metastasis xenograft model in vivo\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo xenograft; single lab\",\n      \"pmids\": [\"34743935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assays; USP18 myeloid-specific deletion; in vitro macrophage polarization assays; tumor growth assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus myeloid-conditional KO; single lab, multiple methods\",\n      \"pmids\": [\"38100351\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP18 is a bifunctional protein that (1) specifically cleaves ISG15 from ISGylated substrates via its catalytic cysteine (with minimal activity toward ubiquitin, particularly in humans), and (2) acts as a scaffold that, when recruited to IFNAR2 by STAT2, sterically blocks JAK1 access to the receptor and thereby negatively regulates type I IFN signaling independently of its catalytic activity; additionally, it deubiquitinates multiple substrates (TAK1, NEMO, STING via USP20 recruitment, MAVS-related TRIM31 scaffolding, Notch1, Twist1, ZEB1, SOX9, FTO, cGAS, SLC7A11, KRAS, PTEN, FOXO3a) to modulate NF-κB, antiviral, metabolic, and oncogenic pathways, while its own stability is controlled by ISG15-mediated protection from SKP2-dependent proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #5]. 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 [#0]. 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 [#1]. 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 [#2, #3, #4, #7]. 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 [#5, #19, #26]. This scaffold function maintains microglial quiescence against tonic IFN signaling [#6]. Beyond interferon, USP18 deubiquitinates components of innate immune and inflammatory signaling — removing K63-linked chains from TAK1 to restrain NF-\\u03baB/NFAT and Th17-driven autoimmunity [#9, #15], binding NEMO to limit IKK activation [#10], and acting as a scaffold to recruit USP20 to deubiquitinate and stabilize STING and to re-localize TRIM31 to mitochondria to potentiate MAVS [#8, #11]. Its own stability is governed by ISG15, which competes with SKP2 to protect USP18 from SCF-SKP2\\u2013mediated proteasomal degradation [#29, #16]. 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 [#28, #22, #34, #21, #32, #20, #25, #17, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the basic identity of USP18 as a USP-family deubiquitinating enzyme and its nuclear localization, providing the molecular starting point.\",\n      \"evidence\": \"cDNA cloning and immunofluorescence of tagged constructs in transfected human cells\",\n      \"pmids\": [\"10777664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define substrate specificity\", \"Did not address non-nuclear isoforms or functions\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved what USP18 actually cleaves, identifying it as the major ISG15-specific protease rather than a general deubiquitinase.\",\n      \"evidence\": \"In vitro protease assays with multiple Ubl substrates, self-processing assay, and USP18 knockout mouse\",\n      \"pmids\": [\"11788588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain the structural basis for ISG15 over ubiquitin selectivity\", \"Did not address non-catalytic functions\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked USP18 to the antiviral IFN response by showing its knockdown potentiates IFN-\\u03b1 suppression of HCV replication.\",\n      \"evidence\": \"siRNA knockdown with HCV replicon/virus and STAT1 phosphorylation readouts in human cells\",\n      \"pmids\": [\"17101330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not separate ISGylation effects from receptor-level signaling effects\", \"Single-lab loss-of-function\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified USP18 as the dominant mediator of sustained, long-lasting refractoriness of IFN-\\u03b1 JAK-STAT signaling in vivo, distinct from SOCS-mediated early termination.\",\n      \"evidence\": \"Repeated IFN-\\u03b1 injection with genetic epistasis across USP18, SOCS1, and SOCS3 knockout mice\",\n      \"pmids\": [\"19564419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular mechanism at the receptor\", \"Did not establish whether catalytic activity is required\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Localized USP18's negative regulation to the receptor level, showing it impairs IFN-\\u03b12 binding-site formation at IFNAR2 and underlies differential IFN desensitization.\",\n      \"evidence\": \"Overexpression/RNAi with receptor-binding and signaling readouts in cell lines\",\n      \"pmids\": [\"21779393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the adaptor recruiting USP18 to the receptor\", \"Did not resolve catalytic requirement\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed alternative translation initiation producing a nuclear short isoform with enhanced deISGylation activity, indicating isoform-specific functional compartmentalization.\",\n      \"evidence\": \"Start-codon mutagenesis, IRES reporter assays, fractionation, and in vitro deISGylation comparing isoforms\",\n      \"pmids\": [\"22170061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of the short isoform not established in vivo\", \"Single-study observation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetically separated USP18's two activities, proving that suppression of IFN signaling is catalysis-independent while ISGylation and antiviral resistance require the isopeptidase.\",\n      \"evidence\": \"Catalytically inactive C61A knock-in mice with ISG15 KO epistasis and viral challenge\",\n      \"pmids\": [\"25605921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the scaffold molecular mechanism\", \"Did not map the protein interface used for non-catalytic function\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that USP18's catalysis-independent, IFNAR2-dependent function maintains microglial quiescence against tonic IFN signaling.\",\n      \"evidence\": \"Microglia-conditional Usp18 KO with IFNAR1/IFNAR2 epistasis and catalytic-inactive rescue\",\n      \"pmids\": [\"25896511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the receptor-proximal molecular block\", \"Source of tonic IFN not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified TAK1 as a catalytic substrate, linking USP18 to NF-\\u03baB/NFAT restraint and Th17-driven autoimmunity.\",\n      \"evidence\": \"Co-IP, in vitro deubiquitination, USP18 KO T cells, and EAE model\",\n      \"pmids\": [\"23825189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether scaffold or catalytic mechanism dominates in other cell types\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed USP18 uses two distinct mechanisms against NF-\\u03baB: protease-dependent TAK1 deubiquitination and protease-independent NEMO/UBAN binding.\",\n      \"evidence\": \"Co-IP, in vitro DUB assay, and UBAN-binding mutation analysis in human macrophages\",\n      \"pmids\": [\"26240016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NEMO interface not structurally defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established USP18 as a scaffold that recruits a partner DUB (USP20) to stabilize STING, defining a non-catalytic mode of substrate deubiquitination.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro DUB assay, KO rescue, and in vivo HSV-1 infection\",\n      \"pmids\": [\"27801882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how USP18 selects USP20 over other DUBs\", \"Structural basis of the ternary complex unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the structural basis for ISG15 specificity, showing USP18 recognizes only the C-terminal Ubl domain via a hydrophobic patch.\",\n      \"evidence\": \"X-ray crystallography of USP18 alone and USP18\\u2013ISG15 with mutational validation\",\n      \"pmids\": [\"28165509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures are of mouse protein; human catalytic weakness not yet structurally explained\", \"Did not capture the STAT2/IFNAR2 scaffold interface\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified STAT2 as the essential adaptor recruiting USP18 to IFNAR2, explaining how the catalysis-independent feedback is targeted to the receptor.\",\n      \"evidence\": \"Reciprocal Co-IP and functional reconstitution in human and mouse cells\",\n      \"pmids\": [\"28165510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet show the JAK1-blocking step directly\", \"STAT2-binding interface on USP18 not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended USP18 substrate range to PTEN, showing deISGylation stabilizes cytoplasmic PTEN.\",\n      \"evidence\": \"RPPA, CHX chase, Co-IP for ISG15-PTEN conjugation, and fractionation with KD/OE\",\n      \"pmids\": [\"27980214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance not established\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a catalysis-dependent metabolic role: USP18 deubiquitinates TAK1 to protect against hepatic steatosis and insulin resistance.\",\n      \"evidence\": \"Co-IP, in vitro DUB assay, hepatocyte-specific transgenic/KO mice, and active-site mutant rescue\",\n      \"pmids\": [\"28718215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile catalytic requirement here with catalysis-independent TAK1/NEMO mechanisms reported elsewhere\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the regulation of USP18 stability, showing ISG15 protects USP18 from SKP2-dependent proteasomal degradation in a reciprocal relationship linked to cell cycle progression.\",\n      \"evidence\": \"Co-IP, OE/silencing, proteasome inhibition, and flow cytometry cell cycle analysis\",\n      \"pmids\": [\"30858391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cell-cycle substrate of USP18 not identified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added FOXO3a as a deISGylation target, linking USP18 to fibrosis signaling.\",\n      \"evidence\": \"ISGylation assays, CHX chase, proteasome inhibition, and fibronectin readout in lung fibroblasts\",\n      \"pmids\": [\"31874933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo fibrosis role not tested\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Patient mutation analysis with functional complementation and signaling assays in patient cells\",\n      \"pmids\": [\"32092142\", \"31940699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the USP18\\u2013IFNAR2\\u2013JAK1 arrangement not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed nuclear USP18 shapes the cancer enhancer landscape and limits STAT2-driven ISG/NF-\\u03baB transcription, with depletion triggering pyroptosis.\",\n      \"evidence\": \"ChIP-seq/ATAC-seq, USP18 KO in cancer lines, transcriptomics, and pyroptosis assays\",\n      \"pmids\": [\"36646704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting nuclear USP18 to chromatin not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected USP18/SKP2 to p21 and SAMHD1 regulation, promoting HIV-1 reverse transcription in myeloid cells.\",\n      \"evidence\": \"Co-IP, CRISPR KO, dNTP and SAMHD1 phosphorylation assays, HIV-1 replication\",\n      \"pmids\": [\"30068654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between USP18 and p21 turnover not established\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a mitochondrial scaffold function in which USP18 re-localizes TRIM31 to potentiate MAVS-dependent antiviral IFN, independent of enzymatic activity.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, fractionation, and Usp18 KO mice with SeV/EMCV\",\n      \"pmids\": [\"34016972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP18 partitions between receptor, mitochondria, and nucleus not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed USP18 stabilizes SOX9 to drive reactive astrogliosis and is itself a Hedgehog/Gli2 transcriptional target.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, astrocyte-conditional KO, AAV overexpression, and ChIP\",\n      \"pmids\": [\"33694203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic vs scaffold requirement for SOX9 stabilization not dissected\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Used a patient I60N variant to prove the STAT2-binding scaffold interface is functionally separable from the catalytic domain and from ISG15-mediated stabilization.\",\n      \"evidence\": \"Patient variant analysis, Co-IP with STAT2/IFNAR2, ISG15 stabilization, and signaling assays\",\n      \"pmids\": [\"35258551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic mapping of the STAT2-binding surface not provided\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded oncogenic substrate stabilization, with USP18 deubiquitinating Notch1, ZEB1, and cGAS to promote tumor progression, EMT, and drug resistance.\",\n      \"evidence\": \"Co-IP, K48-chain ubiquitination assays, and in vivo xenograft/metastasis models\",\n      \"pmids\": [\"33051403\", \"34743935\", \"37478666\", \"37422930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic vs scaffold mechanism not consistently dissected across substrates\", \"Each link rests on single-lab studies\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked USP18 to RNA epigenetics, stabilizing FTO to lower m6A on SIRT6 mRNA and drive neuroprotective mitophagy.\",\n      \"evidence\": \"Co-IP, MeRIP/RIP m6A assays, OGD/R and MCAO models with epistasis\",\n      \"pmids\": [\"38340205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deubiquitination biochemistry on FTO limited\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Biochemical human vs mouse activity assays and I60N vs C64S mutant comparison with cellular readouts\",\n      \"pmids\": [\"38632987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural explanation for weak human catalysis not provided\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified non-IFN substrate axes: USP18 stabilizes SLC7A11 to limit ferroptosis and recruits MIB2 to drive autophagic GSDMD degradation, antagonizing pyroptosis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, site-directed mutagenesis (GSDMD K168), KO/OE, and in vivo inflammation/ferroptosis models\",\n      \"pmids\": [\"38959043\", \"38779488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these are direct catalytic or scaffold-mediated events not fully resolved\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the USP18\\u2013IFNAR2\\u2013JAK1 assembly\", \"Catalytic vs scaffold requirement not dissected for most reported substrates\", \"Spatial regulation between compartments unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 9, 15, 28, 34]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 8, 11, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [30, 13, 18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 4, 7, 9, 8, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 29, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14, 23, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [22, 28, 34, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STAT2\", \"IFNAR2\", \"USP20\", \"TAK1\", \"NEMO\", \"SKP2\", \"TRIM31\", \"ISG15\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}