PXD068694

PXD068694 is an original dataset announced via ProteomeXchange.

Title	Membrane tethering by the host ER-resident GTPase Atlastin-2 is critical for flavivirus replication
Description	Flaviviruses (genus Orthoflavivirus) are arthropod-borne viruses which cause approximately 400 million annual global infections in humans. As obligate intracellular pathogens, flaviviruses must co-opt cellular machinery to facilitate their infection and spread. Notably, all flaviviruses replicate in association with the host endoplasmic reticulum (ER); genome replication, sequestered within virus-induced ER invaginations called viral replication organelles (vROs), is coupled to viral assembly, which occurs on ER membranes juxtaposed to sites of vRO formation. Owing to the ER’s incredible topological complexity, ER remodeling proteins exert considerable influence in the regulation of flavivirus infections. We previously reported that the cellular ER remodeling protein Atlastin-2 (ATL2), normally responsible for fusing homotypic ER tubules, is critical for the replication of multiple flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV). However, a mechanistic explanation for the function of ATL2 during infection was unclear. In this work, we report on the conserved role that ATL2 plays in facilitating the spatial organization of flavivirus replication. Immunofluorescence and electron microscopy indicated that ATL2 knockdown resulted in significant vRO spatial dysregulation in both DENV- and ZIKV-infected cells, with an accompanying decrease in virus production and increase in the activation of cellular innate immune responses as vRO formation was disrupted. Correlative light and electron microscopy demonstrated that ATL2 concentrated in areas of vRO formation during flavivirus infection. ATL2 mutational analysis showed that tethering-competent but fusion-defective ATL2 was sufficient to rescue DENV and ZIKV replication in ATL2-knockout cells. Finally, a synthetic peptide that inhibited ATL2 activity significantly reduced DENV replication in cell culture and in human primary cells. Taken together, these results show that ATL2 plays a critical and conserved role in flavivirus infection, with its membrane tethering activity functioning to organize membranes for vRO biogenesis. Importantly, this function can be targeted to inhibit viral replication.
HostingRepository	PRIDE
AnnounceDate	2026-08-18
AnnouncementXML	Submission_2026-08-18_08:26:10.468.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Pietro Scaturro
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-22 10:43:48	ID requested
⏵ 1	2026-08-18 08:26:11	announced

10.1101/2025.11.26.690702;

Owen JE, Bemis CL, Wang Q, Varadan AC, Vander Velden JW, Anda, č, i, ć L, Uyar O, Gupta M, Scharer CD, Chatel-Chaix L, Scaturro P, Suthar MS, Neufeldt CJ, Homotypic endoplasmic reticulum membrane tethering is critical for flavivirus replication. bioRxiv, ():(2025) [pubmed]

submitter keyword: ATL2,Orthoflavivirus, ER remodeling

Pietro Scaturro
contact affiliation	Leibniz Institute for Virology
contact email	pietro.scaturro@leibniz-liv.de
lab head
Pietro Scaturro
contact affiliation	Systems Arbovirology, Leibniz Institute of Virology
contact email	pietro.scaturro@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD068694
     1. Label: PRIDE project
     2. Name: Membrane tethering by the host ER-resident GTPase Atlastin-2 is critical for flavivirus replication