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PXD044082

PXD044082 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple immune pathways
DescriptionHuman cytomegalovirus (HCMV) is a major human pathogen whose life-long persistence is enabled by its remarkable capacity to systematically subvert host immune defences. In exploring the finding that HCMV infection upregulates tumor necrosis factor receptor 2 (TNFR2), a ligand for the proinflammatory anti-viral cytokine TNFa, we discovered the underlying mechanism was due to targeting of the protease, A Disintegrin And Metalloproteinase 17 (ADAM17). ADAM17 is the prototype ‘sheddase, a family of proteases that cleaves other membrane-bound proteins to release biologically active ectodomains into the supernatant. HCMV impaired ADAM17 surface expression through the action of two virally-encoded proteins in its UL/b’ region, UL148 and UL148D. Proteomic plasma membrane profiling of cells infected with a HCMV double deletion mutant for UL148 and UL148D with restored ADAM17 expression, combined with ADAM17 functional blockade, showed that HCMV stabilized the surface expression of 114 proteins (p<0.05) in an ADAM17-dependent fashion. These included known substrates of ADAM17 with established immunological functions such as TNFR2 and Jagged1, but also numerous novel host and viral targets, such as Nectin1, UL8 and UL144. Regulation of TNFa-induced cytokine responses and NK inhibition during HCMV infection were dependent on this impairment of ADAM17. We therefore identify a viral immunoregulatory mechanism in which targeting a single sheddase enables broad regulation of multiple critical surface receptors, revealing a paradigm for viral-encoded immunomodulation.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_06:05:38.835.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterMichael Weekes
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Cytomegalovirus; NCBI TaxID: NCBITaxon:10358;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-07-25 13:37:55ID requested
12023-10-11 07:08:54announced
22023-11-14 09:06:01announced2023-11-14: Updated project metadata.
32024-10-22 06:05:39announced2024-10-22: Updated project metadata.
Publication List
Rubina A, Patel M, Nightingale K, Potts M, Fielding CA, Kollnberger S, Lau B, Ladell K, Miners KL, Nichols J, Nobre L, Roberts D, Trinca TM, Twohig JP, Vlahava VM, Davison AJ, Price DA, Tomasec P, Wilkinson GWG, Weekes MP, Stanton RJ, Wang ECY, ADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple immune pathways. Proc Natl Acad Sci U S A, 120(33):e2303155120(2023) [pubmed]
10.1073/pnas.2303155120;
Keyword List
submitter keyword: UL148, TNFR2, immune, ADAM17, Natural killer cell,Human cytomegalovirus
Contact List
Michael Weekes
contact affiliationCambridge Institute for Medical Research, University of Cambridge
contact emailmpw1001@cam.ac.uk
lab head
Michael Weekes
contact affiliationUniversity of Cambridge
contact emailmpw1001@cam.ac.uk
dataset submitter
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