PXD063404-1

PXD063404 is an original dataset announced via ProteomeXchange.

Title	A genus-wide interaction atlas across NS4B orthologues identifies a conserved role for UFMylation in orthoflavivirus replication (NS4B Effectome - Global Proteome)
Description	Orthoflavivirus infections represent an increasing public health burden, with several members of the genus emerging or re-emerging globally. Despite the availability of few vaccines, no antiviral drugs are currently licensed for the treatment of orthoflavivirus infections. Several pre-clinical studies identified the non-structural protein 4B (NS4B), one of the least characterized viral proteins within the orthoflavivirus genus, as the most promising target for the development of potent direct-acting antivirals. However, its functional roles in viral replication are still elusive. Here, we employ an integrated proteomic approach to systematically identify cellular targets of NS4B across eight prototypic orthoflaviviruses and characterize their influence on the human proteome. Using this approach, we mapped high-confidence NS4B-interacting human proteins across the genus, underlying potentially divergent mechanisms of host adaptation across orthoflaviviruses spanning diverse pathologies and vector preferences. Among these, we unveil a novel function for UBA5, the E1-activating enzyme of the UFMylation pathway, in orthoflavivirus replication. Mechanistically, we map associations of distinct viral proteins with multiple members of the UFMylation pathway, which are selectively recruited to sites of viral replication to promote mitochondrial respiration. Finally, we demonstrate that pharmacological inhibition of UFMylation exerts potent antiviral activity in vitro and in vivo. This integrative study provides a rational framework for a system-level understanding of orthoflavivirus NS4B effector functions and sheds light on a conserved and unconventional role for UFMylation in orthoflavivirus replication.
HostingRepository	PRIDE
AnnounceDate	2026-03-11
AnnouncementXML	Submission_2026-03-10_21:16:50.279.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Pietro Scaturro
SpeciesList	scientific name: Orthoflavivirus; NCBI TaxID: NCBITaxon:3044782; scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	carbamoylated residue; acetylated residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-28 10:25:47	ID requested
⏵ 1	2026-03-10 21:16:50	announced

10.1038/S41467-026-70437-9;

submitter keyword: None

Pietro, Scaturro
contact affiliation	Systems Arbovirology, Leibniz Institute of Virology, Hamburg, Germany
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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/03/PXD063404

PRIDE project URI

• PRIDE
  1. PXD063404
     1. Label: PRIDE project
     2. Name: A genus-wide interaction atlas across NS4B orthologues identifies a conserved role for UFMylation in orthoflavivirus replication (NS4B Effectome - Global Proteome)