ArticleProceedings of the National Academy of Sciences of the United States of America2024
Zika virus NS5 protein inhibits type I interferon signaling via CRL3 E3 ubiquitin ligase-mediated degradation of STAT2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed.
- Alphavirus M1 disrupts super-enhancer-driven oncogenic transcription via non-structural protein NSP2 in osteosarcoma.Nature communications · 2026Article
- Virus-host interactome reveals host cellular pathways perturbed by tick-borne encephalitis virus infection.iScience · 2026Article
- Review
- A dual-pronged host-directed therapeutic targeting cyclophilin A and pathogenic interferon response abrogates virus-triggered pregnancy pathologies.Nature communications · 2026Article
- mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth.Genes & development · 2026Article
- Article
- NSP1 of Alongshan virus antagonizes type I interferon responses by promoting STUB1-mediated degradation of RIG-I.Cell communication and signaling : CCS · 2026Article
- EIF4H and YBX1 are essential host factors for hepatitis E virus replication and pathogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Article
- FGFR signaling and neddylation facilitate SARS-CoV-2 infection by modulating interferon induction and viral entry, respectively.iScience · 2026Article
- The E3 ubiquitin ligase mechanism specifying target-directed microRNA degradation.bioRxiv : the preprint server for biology · 2026Article
- Differential expression of miRNAs in Vero cells after Mayaro virus infection.Memorias do Instituto Oswaldo Cruz · 2026Article
- Comparative analysis of placental transmission mechanisms for Dengue and Zika viruses: outcomes and future directions.Frontiers in immunology · 2026Review
- Zika virus and host protein interactions for understanding molecular mechanisms of pathogenesis and therapeutic development.Frontiers in cellular and infection microbiology · 2026Review
- Interplay between flaviviruses and the interferon response: mechanisms of immune evasion and therapeutic implications.Frontiers in pharmacology · 2026Review
- LC3-dependent intercellular transfer of phosphorylated STAT1/2 elicits CXCL9+ macrophages and enhances radiation-induced antitumor immunity.The Journal of clinical investigation · 2025Article
- mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth.bioRxiv : the preprint server for biology · 2025Article
- Pathogen virulence genes: Advances, challenges and future directions in infectious disease research (Review).International journal of molecular medicine · 2025Review
- Activation of PD-1/PD-L1 immune checkpoint by Zika virus.PLoS pathogens · 2025Article
- Zika virus disrupts steroidogenesis and impairs spermatogenesis by stalling the translation of CYP17A1 mRNA.Nature communications · 2025Article
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11 authors.
Funding
Abstract
The ZIKA virus (ZIKV) evades the host immune response by degrading STAT2 through its NS5 protein, thereby inhibiting type I interferon (IFN)-mediated antiviral immunity. However, the molecular mechanism underlying this process has remained elusive. In this study, we performed a genome-wide CRISPR/Cas9 screen, revealing that ZSWIM8 as the substrate receptor of Cullin3-RING E3 ligase is required for NS5-mediated STAT2 degradation. Genetic depletion of ZSWIM8 and CUL3 substantially impeded NS5-mediated STAT2 degradation. Biochemical analysis illuminated that NS5 enhances the interaction between STAT2 and the ZSWIM8-CUL3 E3 ligase complex, thereby facilitating STAT2 ubiquitination. Moreover, ZSWIM8 knockout endowed A549 and Huh7 cells with partial resistance to ZIKV infection and protected cells from the cytopathic effects induced by ZIKV, which was attributed to the restoration of STAT2 levels and the activation of IFN signaling. Subsequent studies in a physiologically relevant model, utilizing human neural progenitor cells, demonstrated that ZSWIM8 depletion reduced ZIKV infection, resulting from enhanced IFN signaling attributed to the sustained levels of STAT2. Our findings shed light on the role of ZIKV NS5, serving as the scaffold protein, reprograms the ZSWIM8-CUL3 E3 ligase complex to orchestrate STAT2 proteasome-dependent degradation, thereby facilitating evasion of IFN antiviral signaling. Our study provides unique insights into ZIKV-host interactions and holds promise for the development of antivirals and prophylactic vaccines.
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