ArticlePLoS pathogens2019
HCV and flaviviruses hijack cellular mechanisms for nuclear STAT2 degradation: Up-regulation of PDLIM2 suppresses the innate immune response.
Article in PLoS pathogens, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Assessment of hepatitis C virus permissiveness in iteratively genetically humanized mice.Journal of virology · 2025Article
- Decoding microbial carcinogenic strategies: ubiquitination and SUMO modification.Frontiers in microbiology · 2025Review
- Residue K28 of Zika Virus NS5 Protein Is Implicated in Virus Replication and Antagonism of STAT2.Microorganisms · 2024Article
- CRISPR/Cas9 as a New Antiviral Strategy for Treating Hepatitis Viral Infections.International journal of molecular sciences · 2023Review
- Structural Investigations of Interactions between the Influenza a Virus NS1 and Host Cellular Proteins.Viruses · 2023Review
- African Swine Fever Virus Cysteine Protease pS273R Inhibits Type I Interferon Signaling by Mediating STAT2 Degradation.Journal of virology · 2023Article
- Article
- Hepatitis C Virus Reactivation in Anti-HCV Antibody-Positive Patients with Chronic Hepatitis B Following Anti-HBV Therapies.Viruses · 2022Article
- The unexpected versatility of ALP/Enigma family proteins.Frontiers in cell and developmental biology · 2022Review
- PDLIM2: Signaling pathways and functions in cancer suppression and host immunity.Biochimica et biophysica acta. Reviews on cancer · 2021Review
- Review
- Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy.Journal of clinical immunology · 2021Review
- Suppression of JAK-STAT Signaling by Epstein-Barr Virus Tegument Protein BGLF2 through Recruitment of SHP1 Phosphatase and Promotion of STAT2 Degradation.Journal of virology · 2021Article
- Central Nervous System-Infecting Pathogens Escherichia coli and Cryptococcus neoformans Exploit the Host Pdlim2 for Intracellular Traversal and Exocytosis in the Blood-Brain Barrier.Infection and immunity · 2021Article
- Antiviral strategies targeting host factors and mechanisms obliging +ssRNA viral pathogens.Bioorganic & medicinal chemistry · 2021Review
- Endoplasmic Reticulum-Associated Degradation Controls Virus Protein Homeostasis, Which Is Required for Flavivirus Propagation.Journal of virology · 2021Article
- Review
- Acute Infection of Viral Pathogens and Their Innate Immune Escape.Frontiers in microbiology · 2021Review
- Duck Tembusu Virus Infection Promotes the Expression of Duck Interferon-Induced Protein 35 to Counteract RIG-I Antiviral Signaling in Duck Embryo Fibroblasts.Frontiers in immunology · 2021Article
- Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Host encounters with viruses lead to an innate immune response that must be rapid and broadly targeted but also tightly regulated to avoid the detrimental effects of unregulated interferon expression. Viral stimulation of host negative regulatory mechanisms is an alternate method of suppressing the host innate immune response. We examined three key mediators of the innate immune response: NF-KB, STAT1 and STAT2 during HCV infection in order to investigate the paradoxical induction of an innate immune response by HCV despite a multitude of mechanisms combating the host response. During infection, we find that all three are repressed only in HCV infected cells but not in uninfected bystander cells, both in vivo in chimeric mouse livers and in cultured Huh7.5 cells after IFNα treatment. We show here that HCV and Flaviviruses suppress the innate immune response by upregulation of PDLIM2, independent of the host interferon response. We show PDLIM2 is an E3 ubiquitin ligase that also acts to stimulate nuclear degradation of STAT2. Interferon dependent relocalization of STAT1/2 to the nucleus leads to PDLIM2 ubiquitination of STAT2 but not STAT1 and the proteasome-dependent degradation of STAT2, predominantly within the nucleus. CRISPR/Cas9 knockout of PDLIM2 results in increased levels of STAT2 following IFNα treatment, retention of STAT2 within the nucleus of HCV infected cells after IFNα stimulation, increased interferon response, and increased resistance to infection by several flaviviruses, indicating that PDLIM2 is a global regulator of the interferon response.
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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.