PXD017092

PXD017092 is an original dataset announced via ProteomeXchange.

Title	Complement C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodelling.
Description	Critical illness is characterised by organ failure, dysregulated immune activation and frequent secondary infections. Unbridled complement activation in these patients exposes immune cells to high levels of the anaphylotoxin, C5a. C5a suppresses antimicrobial functions of key immune cells, in particular the neutrophil, and this suppression is associated with poorer outcomes amongst critically ill adults. The intracellular signalling pathways which mediate C5a-induced neutrophil dysfunction are incompletely understood. Healthy donor peripheral blood neutrophils exposed to purified C5a demonstrated a prolonged defect in phagocytosis of the common nosocomial pathogen Staphylococcus aureus which persisted for 7 hours after exposure. Phosphoproteomic profiling of 2712 unique phosphoproteins identified persistent C5a signalling at 1 hour, and selective impairment of phagosomal protein phosphorylation on exposure to S. aureus. Notable proteins included early endosomal marker ZFYVE16 and V-ATPase proton channel component ATPV1G1. A multi-function assay of bacterial ingestion and phagosomal acidification demonstrated C5a-induced impairment of phagosomal acidification in a whole blood model of Staphylococcal bacteraemia which was recapitulated in neutrophils from critically ill patients. Examination of the C5a-impaired protein phosphorylation indicated a role for the phosphatidylinositol 3-kinase VPS34 in phagosomal maturation. Inhibition of VPS34 impaired neutrophil phagosomal acidification, late bacterial ingestion and killing of S. aureus in whole blood. This study provides a deep phosphoproteomic assessment of human neutrophil signalling in response to S. aureus, and demonstrates how some of these pathways are disrupted by exposure to C5a, identifying a defect in phagosomal maturation and providing new information on mechanisms of immune failure in critical illness.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:10:23.300.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Carmen Gonzalez Tejedo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	methylthiolated residue; phosphorylated residue; monohydroxylated residue; deamidated residue
Instrument	Orbitrap Fusion Lumos; Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-01-14 07:36:13	ID requested
1	2020-08-05 23:01:14	announced
⏵ 2	2024-10-22 05:10:31	announced	2024-10-22: Updated project metadata.

Wood AJ, Vassallo AM, Ruchaud-Sparagano MH, Scott J, Zinnato C, Gonzalez-Tejedo C, Kishore K, D'Santos CS, Simpson AJ, Menon DK, Summers C, Chilvers ER, Okkenhaug K, Morris AC, C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling. JCI Insight, 5(15):(2020) [pubmed]

10.1172/jci.insight.137029;

submitter keyword: Critical care,Neutrophils, Staphylococcus aureus, Complement system proteins, Phosphoproteome

Andrew Conway Morris
contact affiliation	Department of Medicine, University of Cambridge, Cambridge, UK
contact email	ac926@cam.ac.uk
lab head
Carmen Gonzalez Tejedo
contact affiliation	Cancer Research UK Cambridge Institute
contact email	Carmen.GonzalezTejedo@cruk.cam.ac.uk
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/2020/08/PXD017092

PRIDE project URI

• PRIDE
  1. PXD017092
     1. Label: PRIDE project
     2. Name: Complement C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodelling.