ArticlePLoS pathogens2016
Consecutive Inhibition of ISG15 Expression and ISGylation by Cytomegalovirus Regulators.
Article in PLoS pathogens, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 69 citations in OpenAlex.
- Herpesviruses hijack ISGylation to promote viral capsid assembly.Science advances · 2026Article
- Human cytomegalovirus at the maternal-fetal interface: an overview of pathogenesis, defence, and interventions.Clinical science (London, England : 1979) · 2026Review
- Capsaicin Receptor TRPV1 Delays Aortic Aging in Atherosclerotic Mice by Inhibiting the ISG15-p53 Pathway.Journal of cellular and molecular medicine · 2026Article
- Human cytomegalovirus induces neuronal gene expression through IE1 for viral maturation.Nature communications · 2025Article
- Protein-S-nitrosylation of human cytomegalovirus pp65 reduces its ability to undermine cGAS.Journal of virology · 2025Article
- RNA-targeted proteomics identifies YBX1 as critical for efficient HCMV mRNA translation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Recent advances in human cytomegalovirus: a comprehensive review of pathogenic mechanisms, virus-host interactions, and antiviral strategies.Frontiers in immunology · 2025Review
- Human cytomegalovirus: pathogenesis, prevention, and treatment.Molecular biomedicine · 2024Review
- The battle between host antiviral innate immunity and immune evasion by cytomegalovirus.Cellular and molecular life sciences : CMLS · 2024Review
- ISG15/USP18/STAT2 is a molecular hub regulating IFN I-mediated control of Dengue and Zika virus replication.Frontiers in immunology · 2024Article
- Suppression of SARS-CoV-2 nucleocapsid protein dimerization by ISGylation and its counteraction by viral PLpro.Frontiers in microbiology · 2024Article
- ISG15: its roles in SARS-CoV-2 and other viral infections.Trends in microbiology · 2023Review
- On the Value of In Vitro Cell Systems for Mechanobiology from the Perspective of Yes-Associated Protein/Transcriptional Co-Activator with a PDZ-Binding Motif and Focal Adhesion Kinase and Their Involvement in Wound Healing, Cancer, Aging, and Senescence.International journal of molecular sciences · 2023Review
- ISG15 Is Required for the Dissemination of Vaccinia Virus Extracellular Virions.Microbiology spectrum · 2023Article
- Interferon-stimulated gene 15 facilitates BTV replication through interacting with the NS1 protein.Frontiers in microbiology · 2023Article
- β-catenin ISGylation promotes lipid deposition and apoptosis in ethanol-stimulated liver injury models.Redox report : communications in free radical research · 2022Article
- Innate immune regulation in HIV latency models.Retrovirology · 2022Article
- YAP ISGylation increases its stability and promotes its positive regulation on PPP by stimulating 6PGL transcription.Cell death discovery · 2022Article
- ISG15 and ISGylation in Human Diseases.Cells · 2022Review
- Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Interferon-stimulated gene 15 (ISG15) encodes an ubiquitin-like protein that covalently conjugates protein. Protein modification by ISG15 (ISGylation) is known to inhibit the replication of many viruses. However, studies on the viral targets and viral strategies to regulate ISGylation-mediated antiviral responses are limited. In this study, we show that human cytomegalovirus (HCMV) replication is inhibited by ISGylation, but the virus has evolved multiple countermeasures. HCMV-induced ISG15 expression was mitigated by IE1, a viral inhibitor of interferon signaling, however, ISGylation was still strongly upregulated during virus infection. RNA interference of UBE1L (E1), UbcH8 (E2), Herc5 (E3), and UBP43 (ISG15 protease) revealed that ISGylation inhibits HCMV growth by downregulating viral gene expression and virion release in a manner that is more prominent at low multiplicity of infection. A viral regulator pUL26 was found to interact with ISG15, UBE1L, and Herc5, and be ISGylated. ISGylation of pUL26 regulated its stability and inhibited its activities to suppress NF-κB signaling and complement the growth of UL26-null mutant virus. Moreover, pUL26 reciprocally suppressed virus-induced ISGylation independent of its own ISGylation. Consistently, ISGylation was more pronounced in infections with the UL26-deleted mutant virus, whose growth was more sensitive to IFNβ treatment than that of the wild-type virus. Therefore, pUL26 is a viral ISG15 target that also counteracts ISGylation. Our results demonstrate that ISGylation inhibits HCMV growth at multiple steps and that HCMV has evolved countermeasures to suppress ISG15 transcription and protein ISGylation, highlighting the importance of the interplay between virus and ISGylation in productive viral infection.
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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.