PXD044273-1

PXD044273 is an original dataset announced via ProteomeXchange.

Title	Human cytomegalovirus degrades DMXL1 to inhibit autophagy, lysosomal acidification and viral assembly
Description	Human cytomegalovirus (HCMV) is an important human pathogen and a master regulator of host intrinsic, innate, and adaptive immunity. HCMV hijacks host intracellular compartments to assemble new virions, and lysosomes are essential for this process. We combined a comprehensive proteomic analysis of host proteins targeted for degradation by HCMV with a database of proteins involved in vacuolar acidification. Dmx-like protein 1 (DMXL1) was the only protein that acidifies vacuoles yet is degraded by HCMV. Systematic comparison of viral deletion mutants revealed that the uncharacterised 7kDa US33A protein is necessary and sufficient for DMXL1 degradation. Functional experiments using cells stably expressing US33A, or infected with adenovirus vectors expressing US33A, or infected with recombinant HCMV deleted for US33A, demonstrated that HCMV degrades DMXL1 to inhibit lysosomal acidification and autophagic cargo degradation. Formation of the viral assembly compartment, which is known to require lysosomes, occurred significantly later in cells infected with US33A-expressing virus, with reduced viral replication. These data thus identify an entirely new viral strategy for cellular remodelling. US33A recruits the E3 ubiquitin ligase Kip1 ubiquitination-promoting complex (KPC) and acts akin to a proteolysis-targeting chimera (PROTAC) to degrade DMXL1. The potential thus exists to employ US33A in novel therapies for viral infection or rheumatic conditions, in which inhibition of lysosome acidification can attenuate disease.
HostingRepository	PRIDE
AnnounceDate	2024-03-13
AnnouncementXML	Submission_2024-03-13_07:16:02.589.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Michael Weekes
SpeciesList	scientific name: Cytomegalovirus; NCBI TaxID: 10358; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-01 16:20:16	ID requested
⏵ 1	2024-03-13 07:16:02	announced
2	2024-10-22 06:33:12	announced	2024-10-22: Updated project metadata.

10.1016/J.CHOM.2024.02.013;

submitter keyword: proteomics

systems virology

human cytomegalovirus

lysosome

pH

viral replication

viral assembly

autophagy

Professor 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. PXD044273
     1. Label: PRIDE project
     2. Name: Human cytomegalovirus degrades DMXL1 to inhibit autophagy, lysosomal acidification and viral assembly