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dc.contributor.authorIssaian, Aaron
dc.contributor.authorHay, Ariel
dc.contributor.authorDzieciatkowska, Monika
dc.contributor.authorRoberti, Domenico
dc.contributor.authorPerrotta, Silverio
dc.contributor.authorDarula, Zsuzsanna
dc.contributor.authorRedzic, Jasmina
dc.contributor.authorBusch, Micheal P
dc.contributor.authorPage, Grier P
dc.contributor.authorRogers, Stephen C
dc.contributor.authorDoctor, Allan
dc.contributor.authorHansen, Kirk C
dc.contributor.authorEisenmesser, Elan Z
dc.contributor.authorZimring, James C
dc.contributor.authorD'Alessandro, Angelo
dc.date.accessioned2021-05-17T14:45:12Z
dc.date.available2021-05-17T14:45:12Z
dc.date.issued2021-05-13
dc.identifier.urihttp://hdl.handle.net/10713/15662
dc.description.abstractBand 3 (anion exchanger 1 - AE1) is the most abundant membrane protein in red blood cells (RBCs), the most abundant cell in the human body. A compelling model posits that - at high oxygen saturation - the N-term cytosolic domain of AE1 binds to and inhibits glycolytic enzymes, thus diverting metabolic fluxes to the pentose phosphate pathway to generate reducing equivalents. Dysfunction of this mechanism occurs during RBC aging or storage under blood bank conditions, suggesting a role for AE1 in the regulation of blood storage quality and efficacy of transfusion - a life-saving intervention for millions of recipients worldwide. Here we leverage two murine models carrying genetic ablations of AE1 to provide mechanistic evidence of its role in the regulation of erythrocyte metabolism and storage quality. Metabolic observations in mice recapitulated those in a human subject lacking expression of AE11-11 (band 3 Neapolis), while common polymorphisms in the region coding for AE11-56 correlate with increased susceptibility to osmotic hemolysis in healthy blood donors. Through thermal proteome profiling and cross-linking proteomics, we provide a map of the RBC interactome, with a focus on AE11-56 and validate recombinant AE1 interactions with glyceraldehyde 3-phosphate dehydrogenase (GAPDH). As a proof-of-principle and further mechanistic evidence of the role of AE1 in the regulation of redox homeostasis of stored RBCs, we show that incubation with a cell-penetrating AE11-56 peptide can rescue the metabolic defect in glutathione recycling and boost post-transfusion recoveries of stored RBCs from healthy human donors and genetically ablated mice.en_US
dc.description.urihttps://doi.org/10.3324/haematol.2020.278252en_US
dc.language.isoenen_US
dc.publisherFerrata-Storti Foundationen_US
dc.relation.ispartofHaematologicaen_US
dc.subject.meshAnion Exchange Protein 1, Erythrocyteen_US
dc.subject.meshErythrocytes--metabolismen_US
dc.titleThe interactome of the N-terminus of band 3 regulates red blood cell metabolism and storage qualityen_US
dc.typeArticleen_US
dc.identifier.doi10.3324/haematol.2020.278252
dc.identifier.pmid33979990
dc.source.countryItaly


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