PXD019059-1

PXD019059 is an original dataset announced via ProteomeXchange.

Title	Aberrant membrane lipid composition and biophysical properties contribute to impair calcium exchanges in elliptocytosis - A severe case study
Description	Hereditary 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
HostingRepository	PRIDE
AnnounceDate	2020-08-04
AnnouncementXML	Submission_2020-08-03_22:07:47.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD019059
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Didier Vertommen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Met-loss; Met-loss+Acetyl; TMT6plex; Oxidation; Acetyl; Carbamidomethyl
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-05-08 05:49:50	ID requested
⏵ 1	2020-08-03 22:07:47	announced

Dataset with its publication pending

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

Donatienne Tyteca
contact affiliation	UCLouvain, 1200 Brussels, Belgium CELL Unit & PICT imaging Platform, de Duve Institute
contact email	donatienne.tyteca@uclouvain.be
lab head
Didier Vertommen
contact affiliation	UCL - de Duve Institute, Brussels Belgium
contact email	didier.vertommen@uclouvain.be
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD019059
     1. Label: PRIDE project
     2. Name: Aberrant membrane lipid composition and biophysical properties contribute to impair calcium exchanges in elliptocytosis - A severe case study