Biliverdin reductase A is a major determinant of protective NRF2 signaling
Abstract
Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major transcriptional regulator of cellular redox signaling. ChIP-seq and RNA-seq analyses reveal that BVRA and NRF2 coordinate the expression of antioxidant genes, many of which are typically dysregulated in neurodegenerative conditions such as Alzheimer’s disease. Thus, this noncanonical BVRA–NRF2 axis controls an essential pathway of redox signaling in neuroprotection. Our findings position BVRA as a dual-function integrator of antioxidant defense across both lipophilic and hydrophilic compartments, bridging these two distinct modes of redox protection in the brain.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (22)
Chirag Vasavda
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
Ruchita Kothari
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
Navneet Ammal Kaidery
Darby Children’s Research Institute, Medical University of South Carolina
Suwarna Chakraborty
Department of Physiology, Pharmacology, & Therapeutics, Johns Hopkins University School of Medicine
Sunil Jamuna Tripathi
Department of Physiology, Pharmacology, & Therapeutics, Johns Hopkins University School of Medicine
Ryan S. Dhindsa
Cristina Ricco
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
Shruthi Shanmukha
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
Samaneh Saberi
Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina
Julia E. Lefler
Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina
Priyanka Kothari
Department of Cell Biology, Johns Hopkins University School of Medicine
Kalyani Chaubey
Department of Psychiatry, Case Western Reserve University
Adele M. Snowman
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
Michael C. Ostrowski
Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina
Eugenio Barone
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome
Lakshminarayan M. Iyer
Computational Biology Branch, Division of Intramural Research, National Library of Medicine, NIH
L. Aravind
Sudarshana M. Sharma
Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina
Andrew A. Pieper
Department of Psychiatry, Case Western Reserve University
Bobby Thomas
Darby Children’s Research Institute, Medical University of South Carolina
Solomon H. Snyder
Department of Physiology, Pharmacology, & Therapeutics, Johns Hopkins University School of Medicine
Bindu D. Paul
Department of Physiology, Pharmacology, & Therapeutics, Johns Hopkins University School of Medicine