Biology subjects

Issaian, A. V.

Publications and source records attributed to Issaian, A. V..

3 recordsLinked to original sources

bioRxiv2026

A population-scale red blood cell proteome reveals genetically encoded aging clocks predictive of hemolysis and blood donor activity

As the most abundant human cell and the foundation of transfusion medicine, red blood cells (RBCs) offer a unique readout of systemic health, yet they have never been characterized at population scale. We generated a proteome atlas of 13,091 blood donors with multi-omics longitudinal phenotyping, characterizing the influence of demographics and genetic variation on the reproducibility of RBC proteomes across donations. Elastic-net aging clocks captured biological aging with high accuracy and uncovered genetic regulators of {Delta}Age at FN1, C4/IKZF1, CRAT, PFAS, TRIM58. Across independent cohorts, {Delta}Age was accelerated in G6PD deficiency, sickle cell trait/disease, and iron deficiency, reversed by iron repletion, and slowed in high-frequency donors, linking molecular aging to brain iron/myelin and cognitive performance. Molecular aging signatures predicted storage, osmotic, and oxidative hemolysis, hemoglobin increments after transfusion, and long-term donor activity over 12-years. These results establish RBC proteomics as a scalable biomarker of aging, donor healthspan, and transfusion outcomes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/710284v1_ufig1.gif" ALT="Figure 1"> View larger version (96K): org.highwire.dtl.DTLVardef@15bd46eorg.highwire.dtl.DTLVardef@1d7c107org.highwire.dtl.DTLVardef@1c1d870org.highwire.dtl.DTLVardef@168dc6f_HPS_FORMAT_FIGEXP M_FIG Dzieciatkowska et al. generate the first population-scale atlas of the RBC proteome across 13,000 donors and develop proteomic and metabolomic aging clocks that quantify biological age. Molecular {Delta}Age is reproducible across donations, genetically encoded and accelerated in G6PD deficiency, sickle cell trait/disease, and iron deficiency - yet reset by iron repletion, tracking with cognitive function and brain iron/myelin. RBC aging clocks predict hemolytic fragility, transfusion efficacy, and donor activity 12 years later. C_FIG HighlightsO_LIRBC proteome atlas of 13,091 donors reveals demographic and genetic programs C_LIO_LIGenetically encoded RBC aging clocks identify regulators of molecular {Delta}age C_LIO_LIMolecular aging features predict hemolysis and transfusion response across cohorts C_LIO_LIRBC molecular age forecasts long-term donor activity over a 12-year follow-up C_LI

biochemistry↗

bioRxiv2025

Deep Red Blood Cell Proteome Defines the Band 3 N-Terminus Interactome as a Regulator of Hypoxic Adaptation via BLVRB-Dependent S-Nitroso Transfer

Red blood cells (RBCs) have long been regarded as passive oxygen carriers, yet growing evidence reveals a complex, dynamic proteome independent of de novo gene expression. Here, we define the erythrocyte as an oxygen-responsive system organized around a Band 3 (SLC4A1)-centered metabolon. Using deep proteomics of ultra-pure RBCs and cross-linking interactomics, we identify biliverdin reductase B (BLVRB) as a previously unrecognized Band 3 interactor that binds the N-terminal cytosolic domain under normoxia and dissociates under hypoxia, when band 3-deoxyhemoglobin interactions increase threefold. This reversible interaction forms an oxygen-sensitive switch coupling structural, redox, and metabolic remodeling. In humanized mice, truncation of the Band 3 N-terminus disrupted glycolytic activation, reduced 2,3-bisphosphoglycerate synthesis, and impaired exercise tolerance despite preserved cardiopulmonary function, establishing the physiological relevance of this module. Population-scale proteome quantitative trait locus (pQTL) analyses revealed coordinated variation of SLC4A1 and BLVRB abundance but minimal association of biliverdin levels with BLVRB genotype, suggesting alternative functions beyond heme catabolism. Mechanistically, BLVRB Cys109 acts as a nitric oxide (NO) relay, trans-nitrosating glycolytic enzymes such as GAPDH at active site Cys152, transiently inhibiting glycolysis. This S-nitrosation-mediated feedback mirrors conserved mechanisms in plants, where GAPDH-SNO redirects carbon flow toward the Calvin-Benson cycle under nitrosative stress, revealing an evolutionary convergence in gas-responsive metabolic control. Collectively, our findings define a Band 3-BLVRB-hemoglobin axis that links oxygen sensing, NO signaling, and redox homeostasis, providing a unifying model for how an anucleate cell achieves environmental adaptability through reversible protein-protein interactions and post-translational chemistry. Graphic abstractIssaian et al. define the most comprehensive proteome of ultra-pure human red blood cells (3,775 proteins) and map the O2-dependent interactome, revealing a Band 3-BLVRB-hemoglobin module that links oxygen sensing to metabolic remodeling via reversible inhibitory S-nitrosation of GAPDH C152. In plants this redirects carbon toward photosynthesis, illustrating a conserved NO-dependent metabolic reprogramming mechanism across oxygen-regulated systems. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/691178v1_ufig1.gif" ALT="Figure 1"> View larger version (89K): org.highwire.dtl.DTLVardef@122468org.highwire.dtl.DTLVardef@114428dorg.highwire.dtl.DTLVardef@11d40c4org.highwire.dtl.DTLVardef@1870fb7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDeep proteomics defines a complete, contamination-free RBC proteome (3,775 proteins) C_LIO_LICross-linking proteomics maps an oxygen-sensitive Band 3-centered interactome C_LIO_LIO2-dependent BLVRB-Band 3 binding regulates metabolism via S-nitrosation of GAPDH C_LIO_LIBand 3 N-terminus is required for hypoxic remodeling and exercise tolerance in vivo C_LI

biochemistry↗

bioRxiv2025

Genetic variation of human G6PD impacts Red Blood Cell transfusion efficacy

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzymopathy, affects 6% of the global population, yet its impact on blood storage and transfusion efficacy remains undefined. We integrated genome-metabolome-proteome analyses of 13,091 blood donors (362 G6PD SNPs), validated in a recalled cohort (n=643), linked donor-recipient databases, humanized mouse models (canonical, African A- [V68M+N126D], Mediterranean [S188F]), and a prospective sickle cell disease study. Common G6PD variants reduced protein abundance, reprogrammed redox metabolism, and increased storage hemolysis. In mice, G6PD-deficient RBCs showed lower post-transfusion recovery, higher oxidative stress, and impaired renal oxygenation. Clinically, recipients of G6PD-deficient units exhibited smaller hemoglobin increments and reduced RBC L{superscript 1}Cr-survival (-8% at 24 h; -12% at 4 weeks). Structural studies revealed kinetic fragility for A- and thermodynamic fragility for Med-, linking genotype to protein instability and transfusion outcome. These findings identify donor G6PD genotype as a determinant of transfusion efficacy, supporting genotype-aware inventory-management strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/689741v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@1897489org.highwire.dtl.DTLVardef@1420587org.highwire.dtl.DTLVardef@178e8ddorg.highwire.dtl.DTLVardef@1003b44_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗