Coatomer protein complex I is required for efficient secretion of dengue virus non-structural protein 1

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dc.contributor.authorJohnson, S.M.
dc.contributor.authorCentofanti, S.M.
dc.contributor.authorBracho, G.
dc.contributor.authorBeard, M.R.
dc.contributor.authorCarr, J.M.
dc.contributor.authorEyre, N.S.
dc.contributor.editorLuo, G.G.
dc.date.issued2025
dc.description.abstractSecreted non-structural protein 1 (sNS1) is an important orthoflavivirus pathogenic factor that can induce vascular leakage, a key symptom of severe dengue disease. Given the role of sNS1 in dengue pathogenesis, defining the molecular mechanisms of NS1 secretion may contribute to the development of NS1-targeting antiviral therapies. To this end, we performed a customized membrane-trafficking siRNA screen to identify human host factors involved in NS1 secretion. Our screen identified COPA, COPB2, and COPG1 as the top-ranking hits. These proteins are three of the seven subunits of the coatomer protein complex I (COPI) that coat transport vesicles that operate within the early secretory pathway, implicating COPI machinery as being involved in NS1 secretion. Validation studies employing host gene knockdown in dengue virus (DENV)-infected cells confirmed that COPI components are required for efficient NS1 secretion but are dispensable for infectious virus egress. Similar reductions in NS1 secretion were observed when COPI components were depleted in cells infected with West Nile virus Kunjin subtype (WNV/KUNV), indicating that the molecular mechanisms exploited to achieve NS1 secretion may be a conserved feature within the Orthoflavivirus genus. Heterologous expression of wild-type and pathogenic COPI variants in DENV NS1-NS5 polyprotein-expressing cells resulted in altered NS1 secretion profiles, suggesting that allelic variants and altered expression levels of COPI components may indirectly influence the severity of dengue disease. The identification of COPI components as important determinants of NS1 secretion efficiency may aid in the identification of novel targets for anti-orthoflaviviral therapies.
dc.description.statementofresponsibilityStephen M. Johnson, Siena M. Centofanti, Gustavo Bracho, Michael R. Beard, Jillian M. Carr, Nicholas S. Eyre
dc.identifier.citationJournal of Virology, 2025; 99(9):e0096225-1-e0096225-27
dc.identifier.doi10.1128/jvi.00962-25
dc.identifier.issn0022-538X
dc.identifier.issn1098-5514
dc.identifier.orcidBeard, M.R. [0000-0002-4106-1016]
dc.identifier.urihttps://hdl.handle.net/2440/147933
dc.language.isoen
dc.publisherAmerican Society for Microbiology
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1163662
dc.rightsCopyright © 2025 Johnson et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
dc.source.urihttps://doi.org/10.1128/jvi.00962-25
dc.subjectorthoflavivirus; flavivirus; dengue virus; NS1; NS1 secretion
dc.subject.meshCell Line
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshDengue Virus
dc.subject.meshWest Nile virus
dc.subject.meshDengue
dc.subject.meshCoat Protein Complex I
dc.subject.meshViral Nonstructural Proteins
dc.subject.meshRNA, Small Interfering
dc.subject.meshHost-Pathogen Interactions
dc.subject.meshHEK293 Cells
dc.titleCoatomer protein complex I is required for efficient secretion of dengue virus non-structural protein 1
dc.typeJournal article
pubs.publication-statusPublished online

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