ArticlePLoS pathogens2019
A novel interaction between dengue virus nonstructural protein 1 and the NS4A-2K-4B precursor is required for viral RNA replication but not for formation of the membranous replication organelle.
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 67 papers.
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Who cites it
67 citing papers in PubMed, 118 citations in OpenAlex.
- Zika virus produces two isoforms of the NS2A protein that play mutually exclusive roles in viral replication and virion assembly.PLoS pathogens · 2026Article
- Review
- Identification and validation of natural dengue virus NS1 inhibitors with promising antiviral potential.Molecular diversity · 2026Article
- Dynamic structures of dengue virus serotype 2 secreted NS1 and their interactions with heparan sulfate.Nature communications · 2026Article
- Discovery of a potent anti-Zika virus benzamide series targeting the viral protein NS4B.PLoS pathogens · 2026Article
- In vitro synthesis of active recombinant orthoflavivirus nonstructural polyproteins in detergent micelles for biochemical analysis.Npj viruses · 2026Article
- Roles of non-structural protein 1 in dengue virus replication and immunomodulation in vivo.The Journal of veterinary medical science · 2026Article
- Cellular Biology: Virus-Host Interactions and RNA Structure and Function.Current topics in microbiology and immunology · 2026Review
- Pathogenicity and virulence of Powassan virus.Virulence · 2025Review
- Flavivirus NS1-triggered endothelial dysfunction promotes virus dissemination.PLoS pathogens · 2025Article
- Hiding in plain sight: Genomic and phenotypic characterization of mosquito-borne Bussuquara virus.PLoS neglected tropical diseases · 2025Article
- Article
- AlphaFold Prediction of Protein-Protein Interactions in theInternational journal of molecular sciences · 2025Article
- Discovery of a potent anti-Zika virus benzamide series targeting the viral protein NS4B.bioRxiv : the preprint server for biology · 2025Article
- Coatomer protein complex I is required for efficient secretion of dengue virus non-structural protein 1.Journal of virology · 2025Article
- Modes of action of a small molecule antiviral compound targeting yellow fever virus NS4B protein.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Development of New Live-Attenuated Vaccine Candidates Lacking Antibody-Dependent Enhancement (ADE) Against Dengue.Vaccines · 2025Review
- Repurposing of FDA-approved drugs against oligomerization domain of dengue virus NS1 protein: a computational approach.Molecular diversity · 2025Article
- Functional Roles and Host Interactions ofPathogens (Basel, Switzerland) · 2025Review
- Identification of viral protease-dependent cleavage sites within the human astrovirus polyprotein.Journal of virology · 2025Article
7 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dengue virus (DENV) has emerged as major human pathogen. Despite the serious socio-economic impact of DENV-associated diseases, antiviral therapy is missing. DENV replicates in the cytoplasm of infected cells and induces a membranous replication organelle, formed by invaginations of the endoplasmic reticulum membrane and designated vesicle packets (VPs). Nonstructural protein 1 (NS1) of DENV is a multifunctional protein. It is secreted from cells to counteract antiviral immune responses, but also critically contributes to the severe clinical manifestations of dengue. In addition, NS1 is indispensable for viral RNA replication, but the underlying molecular mechanism remains elusive. In this study, we employed a combination of genetic, biochemical and imaging approaches to dissect the determinants in NS1 contributing to its various functions in the viral replication cycle. Several important observations were made. First, we identified a cluster of amino acid residues in the exposed region of the β-ladder domain of NS1 that are essential for NS1 secretion. Second, we revealed a novel interaction of NS1 with the NS4A-2K-4B cleavage intermediate, but not with mature NS4A or NS4B. This interaction is required for RNA replication, with two residues within the connector region of the NS1 "Wing" domain being crucial for binding of the NS4A-2K-4B precursor. By using a polyprotein expression system allowing the formation of VPs in the absence of viral RNA replication, we show that the NS1 -NS4A-2K-4B interaction is not required for VP formation, arguing that the association between these two proteins plays a more direct role in the RNA amplification process. Third, through analysis of polyproteins containing deletions in NS1, and employing a trans-complementation assay, we show that both cis and trans acting elements within NS1 contribute to VP formation, with the capability of NS1 mutants to form VPs correlating with their capability to support RNA replication. In conclusion, these results reveal a direct role of NS1 in VP formation that is independent from RNA replication, and argue for a critical function of a previously unrecognized NS4A-2K-NS4B precursor specifically interacting with NS1 and promoting viral RNA replication.
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