ArticlePathogens (Basel, Switzerland)2022
Flavivirus NS1 Triggers Tissue-Specific Disassembly of Intercellular Junctions Leading to Barrier Dysfunction and Vascular Leak in a GSK-3β-Dependent Manner.
Article in Pathogens (Basel, Switzerland), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 38 citations in OpenAlex.
- Differential properties of NS1 glycoproteins in West Nile and Usutu viruses.Emerging microbes & infections · 2026Article
- Neutrophils promote endothelial cell activation in pediatric Mycoplasma pneumoniae pneumonia.JCI insight · 2026Article
- Identification and validation of natural dengue virus NS1 inhibitors with promising antiviral potential.Molecular diversity · 2026Article
- Dengue NS1 as a Driver of Immune-Mediated Pathogenesis.Tropical medicine and infectious disease · 2026Review
- A pan-viral map of host dependency factors from multi-omics integration and machine learning across influenza A, SARS-CoV-2, Zika, and dengue viruses.Journal of translational medicine · 2026Article
- Review
- Double-edged sword: flavivirus NS1 enhances human plasmin-mediated fibrinolysis while being targeted for cleavage and inactivation.The Journal of general virology · 2026Article
- The dengue virus NS1 protein altersmBio · 2026Article
- Roles of non-structural protein 1 in dengue virus replication and immunomodulation in vivo.The Journal of veterinary medical science · 2026Article
- Flavivirus NS1-triggered endothelial dysfunction promotes virus dissemination.PLoS pathogens · 2025Article
- Flavivirus Nonstructural Protein 1‑Driven Coagulation via Tissue Factor-Bearing Microvesicles: A Pilot Study.ACS omega · 2025Article
- Dengue Virus NS1 Binds Ephrin B1 to Trigger Endothelial Dysfunction.bioRxiv : the preprint server for biology · 2025Article
- Review
- Exploiting host kinases to combat dengue virus infection and disease.Antiviral research · 2025Review
- Article
- Review
- Zika virus NS1 drives tunneling nanotube formation for mitochondrial transfer and stealth transmission in trophoblasts.Nature communications · 2025Article
- Epidemiological Trends and Public Health Implications of Dengue Fever in Zhejiang Province, China: A Decadal Analysis from National to Cangnan Perspectives.International journal of general medicine · 2025Article
- Tick-borne encephalitis vaccine breakthrough infections induce aberrant T cell and antibody responses to non-structural proteins.NPJ vaccines · 2024Article
- The NS1 protein of contemporary West African Zika virus potentiates viral replication and reduces innate immune activation.PLoS neglected tropical diseases · 2024Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
The flavivirus nonstructural protein 1 (NS1) is secreted from infected cells and contributes to endothelial barrier dysfunction and vascular leak in a tissue-dependent manner. This phenomenon occurs in part via disruption of the endothelial glycocalyx layer (EGL) lining the endothelium. Additionally, we and others have shown that soluble DENV NS1 induces disassembly of intercellular junctions (IJCs), a group of cellular proteins critical for maintaining endothelial homeostasis and regulating vascular permeability; however, the specific mechanisms by which NS1 mediates IJC disruption remain unclear. Here, we investigated the relative contribution of five flavivirus NS1 proteins, from dengue (DENV), Zika (ZIKV), West Nile (WNV), Japanese encephalitis (JEV), and yellow fever (YFV) viruses, to the expression and localization of the intercellular junction proteins β-catenin and VE-cadherin in endothelial cells from human umbilical vein and brain tissues. We found that flavivirus NS1 induced the mislocalization of β-catenin and VE-cadherin in a tissue-dependent manner, reflecting flavivirus disease tropism. Mechanistically, we observed that NS1 treatment of cells triggered internalization of VE-cadherin, likely via clathrin-mediated endocytosis, and phosphorylation of β-catenin, part of a canonical IJC remodeling pathway during breakdown of endothelial barriers that activates glycogen synthase kinase-3β (GSK-3β). Supporting this model, we found that a chemical inhibitor of GSK-3β reduced both NS1-induced permeability of human umbilical vein and brain microvascular endothelial cell monolayers in vitro and vascular leakage in a mouse dorsal intradermal model. These findings provide insight into the molecular mechanisms regulating NS1-mediated endothelial dysfunction and identify GSK-3β as a potential therapeutic target for treatment of vascular leakage during severe dengue disease.
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