The red blood cell proteome and interactome identify a Band 3–BLVRB axis regulating hypoxic metabolic adaptation
16 affiliations
- 11Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz, Aurora, CO
- 22Center for Blood Oxygen Transport and Hemostasis, University of Maryland School of Medicine, Baltimore, MD
- 33Department of Pathology, Carter Immunology Center, University of Virginia, Charlottesville, VA
- 44Department of Pathology, Children’s Hospital Colorado, Aurora, CO
- 55RTI International, Research Triangle Park, NC
- 66Omix Technologies Inc, Aurora, CO
- 77Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Anschutz, Aurora, CO
- 88Structural Biology Initiative, The City University of New York Advanced Science Research Center, New York, NY
- 910Department of Pediatrics, University of California San Diego, La Jolla, CA
- 109Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA
- 1111Department of Chemistry, Wake Forest University, Winston-Salem, NC
- 1212Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD
- 1313Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
- 1414New York Blood Center, New York, NY
- 1515Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- 1616Canadian Blood Center, Vancouver, Canada
Abstract
Red blood cells (RBCs) are transcriptionally silent yet dynamically remodel metabolism in response to oxygen tension. Using ultrapure human RBCs, we generated the deepest contamination-free proteome to date (3775 proteins) and mapped the oxygen-dependent interactome. These data sets revealed an oxygen-responsive metabolon centered on the Band 3 (SLC4A1) N terminus. We identified biliverdin reductase B (BLVRB) as a previously unrecognized Band 3 interactor that dissociates under hypoxia, coincident with increased Band 3-deoxyhemoglobin contacts. This reversible assembly functions as an oxygen-sensitive switch coordinating redox and glycolytic remodeling. Humanized mice lacking Band 3 N-terminal segments exhibited impaired oxygen-dependent regulation of BLVRB binding to Band 3, impaired hypoxic activation of glycolysis, reduced 2,3-bisphosphoglycerate synthesis, and diminished exercise tolerance, demonstrating physiological relevance. Population-scale cis-protein quantitative trait loci for SLC4A1 and BLVRB suggest functions beyond canonical heme catabolism. Mechanistically, in vitro biochemical analyses suggest that hemoglobin β, Band 3, and BLVRB can undergo S-nitrosation and may participate in transnitrosation reactions with the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, whose modification at C152 inhibits enzymatic activity in vitro. Collectively, these findings define a Band 3-BLVRB axis that integrates oxygen-dependent protein interactions with thiol-based redox chemistry, providing a framework for understanding how an anucleate cell achieves metabolic adaptability through reversible protein-protein interactions and posttranslational modification. These findings suggest that the perturbation of the Band 3-BLVRB axis may influence oxygen delivery and metabolic flexibility during hypoxic stress, with potential relevance to high-altitude adaptation, exercise physiology, and cardiopulmonary disease.
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BibTeX
@article{issaian2026blood,
title = {{The red blood cell proteome and interactome identify a Band 3–BLVRB axis regulating hypoxic metabolic adaptation}},
author = {Aaron Issaian and Monika Dzieciątkowska and Shaun G. Bevers and Zohreh Safari and Ariel M. Hay and Francesca Isabelle Cendali and Amy Argabright and Stephen Colin Rogers and Anthony J. Saviola and Jasmina S. Redzic and Eric P. Wartchow and Julie A Reisz Haines and Gregory R. Keele and Zachary B. Haiman and Travis G. Nemkov and Daniel Stephenson and Christina Lisk and Francesca Vallese and Bernhard Ørn Palsson and S. Bruce King and Grier P. Page and Allan Doctor and Krystalyn E. Hudson and Kirk C. Hansen and David C. Irwin and Narla Mohandas and James C. Zimring and Elan Zohar Eisenmesser and Angelo D'Alessandro},
journal = {Blood},
year = {2026},
month = jun,
doi = {10.1182/blood.2025032915},
url = {https://doi.org/10.1182/blood.2025032915},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - The red blood cell proteome and interactome identify a Band 3–BLVRB axis regulating hypoxic metabolic adaptation
AU - Aaron Issaian
AU - Monika Dzieciątkowska
AU - Shaun G. Bevers
AU - Zohreh Safari
AU - Ariel M. Hay
AU - Francesca Isabelle Cendali
AU - Amy Argabright
AU - Stephen Colin Rogers
AU - Anthony J. Saviola
AU - Jasmina S. Redzic
AU - Eric P. Wartchow
AU - Julie A Reisz Haines
AU - Gregory R. Keele
AU - Zachary B. Haiman
AU - Travis G. Nemkov
AU - Daniel Stephenson
AU - Christina Lisk
AU - Francesca Vallese
AU - Bernhard Ørn Palsson
AU - S. Bruce King
AU - Grier P. Page
AU - Allan Doctor
AU - Krystalyn E. Hudson
AU - Kirk C. Hansen
AU - David C. Irwin
AU - Narla Mohandas
AU - James C. Zimring
AU - Elan Zohar Eisenmesser
AU - Angelo D'Alessandro
PY - 2026
DA - 2026/06/01
JO - Blood
DO - 10.1182/blood.2025032915
UR - https://doi.org/10.1182/blood.2025032915
AB - Red blood cells (RBCs) are transcriptionally silent yet dynamically remodel metabolism in response to oxygen tension. Using ultrapure human RBCs, we generated the deepest contamination-free proteome to date (3775 proteins) and mapped the oxygen-dependent interactome. These data sets revealed an oxygen-responsive metabolon centered on the Band 3 (SLC4A1) N terminus. We identified biliverdin reductase B (BLVRB) as a previously unrecognized Band 3 interactor that dissociates under hypoxia, coincident with increased Band 3-deoxyhemoglobin contacts. This reversible assembly functions as an oxygen-sensitive switch coordinating redox and glycolytic remodeling. Humanized mice lacking Band 3 N-terminal segments exhibited impaired oxygen-dependent regulation of BLVRB binding to Band 3, impaired hypoxic activation of glycolysis, reduced 2,3-bisphosphoglycerate synthesis, and diminished exercise tolerance, demonstrating physiological relevance. Population-scale cis-protein quantitative trait loci for SLC4A1 and BLVRB suggest functions beyond canonical heme catabolism. Mechanistically, in vitro biochemical analyses suggest that hemoglobin β, Band 3, and BLVRB can undergo S-nitrosation and may participate in transnitrosation reactions with the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, whose modification at C152 inhibits enzymatic activity in vitro. Collectively, these findings define a Band 3-BLVRB axis that integrates oxygen-dependent protein interactions with thiol-based redox chemistry, providing a framework for understanding how an anucleate cell achieves metabolic adaptability through reversible protein-protein interactions and posttranslational modification. These findings suggest that the perturbation of the Band 3-BLVRB axis may influence oxygen delivery and metabolic flexibility during hypoxic stress, with potential relevance to high-altitude adaptation, exercise physiology, and cardiopulmonary disease.
SN - 0006-4971
SN - 1528-0020
ER -