PXD044082

PXD044082 is an original dataset announced via ProteomeXchange.

Title	ADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple immune pathways
Description	Human 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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:05:38.835.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Michael Weekes
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Cytomegalovirus; NCBI TaxID: NCBITaxon:10358;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-25 13:37:55	ID requested
1	2023-10-11 07:08:54	announced
2	2023-11-14 09:06:01	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-10-22 06:05:39	announced	2024-10-22: Updated project metadata.

10.1073/pnas.2303155120;

submitter keyword: UL148, TNFR2, immune, ADAM17, Natural killer cell,Human cytomegalovirus

Michael Weekes
contact affiliation	Cambridge Institute for Medical Research, University of Cambridge
contact email	mpw1001@cam.ac.uk
lab head
Michael Weekes
contact affiliation	University of Cambridge
contact email	mpw1001@cam.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD044082
     1. Label: PRIDE project
     2. Name: ADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple immune pathways