ArticleProceedings of the National Academy of Sciences of the United States of America2015
Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
81 citing papers in PubMed, 127 citations in OpenAlex.
- USP18 exacerbates myocardial I/R injury by inhibiting Parkin mitophagy through the deubiquitinase PTEN-L.Military Medical Research · 2026Article
- A versatile fluorescent reporter for Usutu virus drug screening and infection tracking.PNAS nexus · 2026Article
- Substrate-Selective Inhibition of the SARS-CoV-2 Papain-Like Protease: Inhibition of Hydrolysis of Human Over Viral Substrates.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
- Role of the miR-340-5p/IRF1/USP18 Axis in Neuroinflammation Associated with Epilepsy.Neurochemical research · 2026Article
- USP24 is a cross-reactive DUB targeting MOV10 to regulate IFN-I production.Nature communications · 2026Article
- Pharmacological inhibition of USP18 improves antibacterial responses and the intracellular control ofFrontiers in immunology · 2026Article
- Systemic inflammatory and metabolic disease progression persists despite prevention of myocarditis inFrontiers in immunology · 2026Article
- High-Throughput Synthesis and Screening of a Cyanimide Library Identifies Selective Inhibitors of ISG15-Specific Protease mUSP18.Angewandte Chemie (International ed. in English) · 2025Article
- DIG-DUBs: mechanisms and functions of ISG15 deconjugation by human and viral cross-reactive ubiquitin proteases.Biochemical Society transactions · 2025Article
- Review
- ISG15-Dependent Stabilisation of USP18 Is Necessary but Not Sufficient to Regulate Type I Interferon Signalling in Humans.European journal of immunology · 2025Article
- Chemical tools to define and manipulate interferon-inducible Ubl protease USP18.Nature communications · 2025Article
- ISGylation and E3 ubiquitin ligases: an Atlantic salmon genetic perspective.Frontiers in immunology · 2025Article
- Usp18 Mediates D-Dopachrome Tautomerase-Induced Astrocytic Inflammation After Spinal Cord Injury.Journal of inflammation research · 2025Article
- ISG15 Drives Immune Pathology and Respiratory Failure during Systemic Lymphocytic Choriomeningitis Virus Infection.Journal of immunology (Baltimore, Md. : 1950) · 2024Article
- APOBEC3-related mutations in the spike protein-encoding region facilitate SARS-CoV-2 evolution.Heliyon · 2024Article
- ISG15 blocks cardiac glycolysis and ensures sufficient mitochondrial energy production during Coxsackievirus B3 infection.Cardiovascular research · 2024Article
- Article
- In the moonlight: non-catalytic functions of ubiquitin and ubiquitin-like proteases.Frontiers in molecular biosciences · 2024Review
- USP16 is an ISG15 cross-reactive deubiquitinase that targets pro-ISG15 and ISGylated proteins involved in metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
21 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 7 institutions in 3 countries.
Funding
Abstract
Protein modification by the ubiquitin-like protein ISG15 is an interferon (IFN) effector system, which plays a major role in antiviral defense. ISG15 modification is counteracted by the isopeptidase USP18, a major negative regulator of IFN signaling, which was also shown to exert its regulatory function in an isopeptidase-independent manner. To dissect enzymatic and nonenzymatic functions of USP18 in vivo, we generated knock-in mice (USP18(C61A/C61A)) expressing enzymatically inactive USP18. USP18(C61A/C61A) mice displayed increased levels of ISG15 conjugates, validating that USP18 is a major ISG15 isopeptidase in vivo. Unlike USP18(-/-) mice, USP18(C61A/C61A) animals did not exhibit morphological abnormalities, fatal IFN hypersensitivity, or increased lethality, clearly showing that major USP18 functions are unrelated to its protease activity. Strikingly, elevated ISGylation in USP18(C61A/C61A) mice was accompanied by increased viral resistance against vaccinia virus and influenza B virus infections. Enhanced resistance upon influenza B infection in USP18(C61A/C61A) mice was completely reversed in USP18(C61A/C61A) mice, which additionally lack ISG15, providing evidence that the observed reduction in viral titers is ISG15 dependent. These results suggest that increasing ISGylation by specific inhibition of USP18 protease activity could constitute a promising antiviral strategy with only a minimal risk of severe adverse effects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.