<<< Full experiment listing

PXD019059

PXD019059 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleAberrant membrane lipid composition and biophysical properties contribute to impair calcium exchanges in elliptocytosis - A severe case study
DescriptionHereditary elliptocytosis is a red blood cell (RBC) disease mainly caused by mutations in spectrin, leading to cytoskeletal destabilization. Although patients with heterozygous mutation in α-spectrin (SPTA1) are asymptomatic, morphological changes and hemolysis are observed upon reduced functional α-spectrin production. The molecular mechanism is unknown. We analyzed the consequences of a α-spectrin mutation in a patient almost exclusively expressing the Pro260 variant of SPTA1 (pEl). pEl RBCs showed decreased size and circularity and increased fragility. The pEl RBC proteome was globally preserved but spectrin density at the cell edges rised and the two membrane anchorage complexes were less segregated. Hence, the pEl membrane was strongly impaired. First, the lipidome was modified, showing decreased phosphatidylserine vs increased lysophosphatidylserine species. Second, although membrane transversal asymmetry was preserved, curvature at the RBC edges and rigidity were increased. Third, sphingomyelin-enriched domains were altered in abundance, membrane:cytoskeleton anchorage and cholesterol content were targeted by the plasmatic acid sphingomyelinase (aSMase). Fourth, membrane calcium exchanges through the mechanosensitive channel PIEZO1 and the efflux pump PMCA were impaired, leading to increased intracellular calcium and ROS, lipid peroxidation and methemoglobin. Mecanistically, increased curvature through lysophosphatidylserine membrane insertion in healthy RBCs abrogated calcium influx. Cholesterol depletion of sphingomyelin-enriched domains by methyl-beta-cyclodextrin in pEl RBCs worsened calcium accumulation whereas aSMase inhibition by amitriptyline did the opposite. Those data indicated that α-spectrin tetramerization defect, lysophosphatidylserine, cholesterol domain depletion and aSMase cooperate to alter membrane properties and calcium exchanges, leading to calcium accumulation and oxidative stress. It could help develop novel therapies
HostingRepositoryPRIDE
AnnounceDate2020-08-04
AnnouncementXMLSubmission_2020-08-03_22:07:47.xml
DigitalObjectIdentifierhttp://dx.doi.org/10.6019/PXD019059
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterDidier Vertommen
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListMet-loss; Met-loss+Acetyl; TMT6plex; Oxidation; Acetyl; Carbamidomethyl
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-05-08 05:49:50ID requested
12020-08-03 22:07:47announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: red blood cell disease, spectrin cytoskeleton, calcium, PIEZO1, PMCA, proteome, lipidome, lipid domains, membrane asymmetry, membrane rigidity, membrane curvature, lysophosphatidylserine, reactive oxygen species, oxidized lipids, polyunsaturated fatty acids, cell fragmentation, cholesterol, ascorbic acid, amitriptyline, BAPTA
Contact List
Donatienne Tyteca
contact affiliationUCLouvain, 1200 Brussels, Belgium CELL Unit & PICT imaging Platform, de Duve Institute
contact emaildonatienne.tyteca@uclouvain.be
lab head
Didier Vertommen
contact affiliationUCL - de Duve Institute, Brussels Belgium
contact emaildidier.vertommen@uclouvain.be
dataset submitter
Full Dataset Link List
Dataset FTP location
PRIDE project URI
Repository Record List
[ + ]