Biology subjects

Paul, B. D.

Publications and source records attributed to Paul, B. D..

4 recordsLinked to original sources

bioRxiv2025

Biliverdin Reductase A is a major determinant of neuroprotective Nrf2 signaling

Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a novel non-enzymatic role for BVRA in redox regulation. We show that BVRA directly interacts with nuclear factor erythroid-derived factor-like 2 (Nrf2), the master regulator of redox homeostasis, to modulate target signaling pathways. ChIP-seq and RNA-seq analyses reveal that this interaction coordinates the expression of neuroprotective genes that are typically dysregulated in Alzheimers disease and other neurodegenerative conditions. Thus, this previously unknown BVRA-Nrf2 axis controls an essential pathway of redox signaling in neuroprotection. Our findings establish BVRA as a dual-function integrator of antioxidant defenses in both the lipophilic and hydrophilic subcellular compartments, bridging these two distinct and critical cellular protection mechanisms in the brain. This advancement in understanding the endogenous antioxidant system of the brain positions the BVRA-Nrf2 axis as a promising therapeutic target for neurodegenerative disease. Significance StatementWe show a non-canonical role for biliverdin reductase A (BVRA), classically known as the biosynthetic enzyme for bilirubin, in nonenzymatic modulation of antioxidant neuroprotective nuclear factor erythroid-derived factor-like 2 (Nrf2) signaling in the brain. Both BVRA and Nrf2 signaling are compromised in neurodegenerative diseases such as Alzheimers disease, and the BVRA-Nrf2 axis offers a new direction for developing neuroprotective therapies.

neuroscience↗

bioRxiv2025

FUNCTIONAL ANALYSIS OF BIPARTITE NRF2 ACTIVATORS THAT OVERCOME FEEDBACK REGULATION FOR AGE-RELATED CHRONIC DISEASES

Activating Nrf2 with small molecules is a promising strategy for countering aging, oxidative stress, inflammation, and various disorders, including neurodegeneration. The primary regulator of Nrf2 protein stability is Keap1, a redox sensor protein and an adapter in the Cullin III ubiquitin ligase complex, which labels Nrf2 for proteasomal degradation. The known Nrf2 activators either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered the most suitable for continuous administration, as non-specific chemical modifiers of Keap1 thiols also modify active thiols on other proteins, thus causing side effects. However, when transitioning from homogeneous to cell-based assays, genuine displacement activators show a significant loss in potency by several orders of magnitude. As we demonstrate here, this offset is due to the presence of high micromolar concentrations of Keap1 in both the cell lines and brain tissue. A potential solution could involve targeted delivery of an alkylating agent to Keap1 to achieve the desired specificity. Transcriptomic analysis of a cell-permeable Nrf2 peptide bearing an alkylating fumarate moiety indicates selective activation of the Nrf2 genetic program, confirming the high specificity of this approach. The Nrf2-triggered genetic program has a feedback regulation mechanism through the activation of Bach1, an Nrf2 transcriptional repressor, which is elevated in age-related neurodegeneration. Thus, a benign bipartite Nrf2 activator with Bach1 inhibition properties is needed for maximal benefits. The recently developed heterocyclic carboxamide, HPPE, shows overlap with the Nrf2 pathway activated by the fumarate-linked Nrf2 peptide and with zinc and tin protoporphyrins, which are recognized inhibitors of Bach1. Therefore, HPPE presents a promising and unique combination of the two desired activities that could be further optimized to treat age-related neurodegeneration. HighlightsO_LIThe decrease in potency for reversible displacement activators of Nrf2 in biological assays is attributed to high micromolar concentrations of Keap1 and competition with endogenous Keap1 client proteins. C_LIO_LINrf2 activators specific for Keap1 should combine a displacement scaffold with a substitution that undergoes intracellular conversion into active pro-oxidant or alkylating species. C_LIO_LICell-permeable fumarate-linked Nrf2 peptide solely activates the Nrf2 antioxidant genetic program, as demonstrated by transcriptomic analysis. C_LIO_LIHPPE, a small bipartite molecule, exhibits properties of both Nrf2 activation and Bach1 inhibition, to bypass feedback regulation by targeting both Keap1 and Bach1. C_LI

biochemistry↗

bioRxiv2025

A Metabolite-Based Resistance Mechanism Against Malaria

Whether jaundice, a common presentation of Plasmodium (P.) falciparum malaria (1-3) arising from the accumulation of circulating bilirubin, represents an adaptive or maladaptive response to Plasmodium spp. infection is not understood (1-3). We found that asymptomatic P. falciparum infection was associated with a >10-fold higher ratio of unconjugated bilirubin over parasite burden, compared to symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) (4) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, via genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1) (5), was protective against malaria in mice. Unconjugated bilirubin inhibited P. falciparum proliferation in red blood cells (RBC) via a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin (Hz) crystallization and compromised the parasites food vacuole. In conclusion, jaundice represents a metabolic response to Plasmodium spp. infection that limits malaria severity.

immunology↗

bioRxiv2020

Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling

Synapses are complex bridges that connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. However, they must remain dynamic in order to adapt to changing inputs. Here, we report that the enzyme biliverdin reductase (BVR) physically links together key molecules in focal adhesion signaling at the synapse. In challenging mice with a battery of neurocognitive tasks, we first discover that BVR null (BVR-/-) mice exhibit profound deficits in learning and memory. We uncover that these deficits may be explained by a loss of focal adhesion signaling that is both transcriptionally and biochemically disrupted in BVR-/- hippocampi. We learn that BVR mediates focal adhesion signaling by physically bridging the initiatory kinases FAK/Pyk2 to the effector kinase Src. Activated Src normally promotes synaptic plasticity by phosphorylating the N-methyl-D-aspartate (NMDA) receptor, but FAK/Pyk2 are unable to bind and stimulate Src without BVR. Src itself is a molecular hub upon which many signaling pathways converge in order to stimulate NMDA neurotransmission, positioning BVR at a prominent intersection of synaptic signaling.

neuroscience↗