Band 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 based on indirect evidence 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 the first direct mechanistic evidence of its role in metabolic regulation and blood storage quality. Observations in mice phenocopied those in a human subject lacking expression of AE1 residues 1 to 11 (band 3 Neapolis), while common polymorphisms in the region coding for AE1 residues 1 to 56 increased susceptibility to osmotic hemolysis in healthy blood donors. Through thermal proteome profiling and cross-linking proteomics, we provide the first comprehensive analysis of the RBC interactome, with a focus on AE1 residues 1 to 56 and validate recombinant AE1 interactions with glyceraldehyde 3phosphate dehydrogenase (GAPDH). Finally, we show that incubation with a cell penetrating AE1 residues 1 to 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, paving the way for the in vivo metabolic manipulation of RBCs facing oxidant stress, a landmark of many diseases.

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