Modulation of nuclear receptor function by cellular redox poise

Carter, Eric L.; Ragsdale, Stephen W.

doi:10.1016/j.jinorgbio.2014.01.005

Cited by 21 publications

(13 citation statements)

References 184 publications

(177 reference statements)

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“…It was shown that REV-ERBb harbors a regulatory disulfide bond in the heme-binding pocket, which dictates the binding of the cofactor and thus the activation of the TF (Gupta and Ragsdale 2011). Although these cysteine residues are not conserved in the closely related REV-ERBa, a similar mechanism might still be in place to control this TF because redox regulation appears to be a common theme in the biology of the nuclear receptor superfamily (Carter and Ragsdale 2014).…”

Section: Redox Control Over the Negative Arm Of The Ttflmentioning

confidence: 99%

Cellular Timekeeping: It’s Redox o’Clock

Milev

Rhee

Reddy

2017

Cold Spring Harb Perspect Biol

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Mounting evidence in recent years supports the extensive interaction between the circadian and redox systems. The existence of such a relationship is not surprising because most organisms, be they diurnal or nocturnal, display daily oscillations in energy intake, locomotor activity, and exposure to exogenous and internally generated oxidants. The transcriptional clock controls the levels of many antioxidant proteins and redox-active cofactors, and, conversely, the cellular redox poise has been shown to feed back to the transcriptional oscillator via redox-sensitive transcription factors and enzymes. However, the circadian cycles in the -sulfinylation of the peroxiredoxin (PRDX) proteins constituted the first example of an autonomous circadian redox oscillation, which occurred independently of the transcriptional clock. Importantly, the high phylogenetic conservation of these rhythms suggests that they might predate the evolution of the transcriptional oscillator, and therefore could be a part of a primordial circadian redox/metabolic oscillator. This discovery forced the reappraisal of the dogmatic transcription-centered view of the clockwork and opened a new avenue of research. Indeed, the investigation into the links between the circadian and redox systems is still in its infancy, and many important questions remain to be addressed.

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Section: Redox Control Over the Negative Arm Of The Ttflmentioning

confidence: 99%

Cellular Timekeeping: It’s Redox o’Clock

Milev

Rhee

Reddy

2017

Cold Spring Harb Perspect Biol

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“…Over 300 different proteins (Go et al, ; Pan et al, ) are known to be subject to changes in functional activity as a consequence of Cys oxidation/reduction processes. This includes mitochondrial proteins (Mailloux, Jin, & Willmore, ), signaling systems (Ray, Huang, & Tsuji, ; Forman, Ursini, & Maiorino, ), and nuclear hormone receptors involved in transcriptional activities (Carter & Ragsdale, ). Such Cys oxidation processes seem to constitute a PTM network that shows complexity and reversibility that might rival other PTM systems such as phosphorylation.…”

Section: A Brief Redox Code Primermentioning

confidence: 99%

Spatial perspectives in the redox code—Mass spectrometric proteomics studies of moonlighting proteins

Pinto

Radulović

Godovac‐Zimmermann

2016

Mass Spectrometry Reviews

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The Redox Code involves specific, reversible oxidative changes in proteins that modulate protein tertiary structure, interactions, trafficking, and activity, and hence couple the proteome to the metabolic/oxidative state of cells. It is currently a major focus of study in cell biology. Recent studies of dynamic cellular spatial reorganization with MS-based subcellular-spatial-razor proteomics reveal that protein constituents of many subcellular structures, including mitochondria, the endoplasmic reticulum, the plasma membrane, and the extracellular matrix, undergo changes in their subcellular abundance/distribution in response to oxidative stress. These proteins are components of a diverse variety of functional processes spatially distributed across cells. Many of the same proteins are involved in response to suppression of DNA replication indicate that oxidative stress is strongly intertwined with DNA replication/proliferation. Both are replete with networks of moonlighting proteins that show coordinated changes in subcellular location and that include primary protein actuators of the redox code involved in the processing of NAD /NADH, NADP /NADPH, Cys/CySS, and GSH/GSSG redox couples. Small groups of key proteins such as {KPNA2, KPNB1, PCNA, PTMA, SET} constitute "spatial switches" that modulate many nuclear processes. Much of the functional response involves subcellular protein trafficking, including nuclear import/export processes, vesicle-mediated trafficking, the endoplasmic reticulum/Golgi pathway, chaperone-assisted processes, and other transport systems. This is not visible to measurements of total protein abundance by transcriptomics or proteomics. Comprehensive pictures of cellular function will require collection of data on the subcellular transport and local functions of many moonlighting proteins, especially of those with critical roles in spatial coordination across cells. The proteome-wide analysis of coordinated changes in abundance and trafficking of proteins offered by MS-based proteomics has a unique, crucial role to play in deciphering the complex adaptive systems that underlie cellular function. © 2016 Wiley Periodicals, Inc. Mass Spec Rev.

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“…The multiple functions of NRs (DNA, ligand, and coregulator binding) are accomplished through their modular structure (22,23). The N-terminal A/B domain is hypervariable, is involved in ligand-independent transcriptional regulation, and is subject to phosphorylation.…”

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confidence: 99%

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

Carter

Gupta

Ragsdale

2016

Journal of Biological Chemistry

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Rev-erb␣ and Rev-erb␤ are heme-binding nuclear receptors (NR) that repress the transcription of genes involved in regulating metabolism, inflammation, and the circadian clock. Previous gene expression and co-immunoprecipitation studies led to a model in which heme binding to Rev-erb␣ recruits nuclear receptor corepressor 1 (NCoR1) into an active repressor complex. However, in contradiction, biochemical and crystallographic studies have shown that heme decreases the affinity of the ligand-binding domain of Rev-erb NRs for NCoR1 peptides. One explanation for this discrepancy is that the ligand-binding domain and NCoR1 peptides used for in vitro studies cannot replicate the key features of the full-length proteins used in cellular studies. However, the combined in vitro and cellular results described here demonstrate that heme does not directly promote interactions between full-length Rev-erb␤ (FLRev-erb␤) and an NCoR1 construct encompassing all three NR interaction domains. NCoR1 tightly binds both apo-and heme-replete FLRev-erb␤⅐DNA complexes; furthermore, heme, at high concentrations, destabilizes the FLRev-erb␤⅐NCoR1 complex. The interaction between FLRev-erb␤ and NCoR1 as well as Reverb␤ repression at the Bmal1 promoter appear to be modulated by another cellular factor(s), at least one of which is related to the ubiquitin-proteasome pathway. Our studies suggest that heme is involved in regulating the degradation of Rev-erb␤ in a manner consistent with its role in circadian rhythm maintenance. Finally, the very slow rate constant (10 ؊6 s ؊1 ) of heme dissociation from Rev-erb␤ rules out a prior proposal that Reverb␤ acts as an intracellular heme sensor.Nuclear receptors (NRs) 2 are eukaryotic transcription factors that activate or repress gene expression in response to binding small signaling molecules such as steroid hormones, lipophilic vitamins, and fatty acids (1). Genes regulated by NRs are involved in a myriad of cellular processes ranging from metabolic homeostasis to growth and development. The subjects of this article, Rev-erb␣ and Rev-erb␤, are NRs that have overlapping functions and tissue expression patterns (2-9) and are under circadian control (10 -12). Rev-erb NRs repress the transcription of key genes, e.g. Bmal1, CLOCK, and Rev-erb␣ itself, involved in regulating the molecular clock (13)(14)(15). This is accomplished in part through the formation of a heterodimeric Bmal1-CLOCK complex that activates the transcription of clock-controlled genes including Rev-erb␣/␤, completing a critical feedback loop required for circadian rhythm maintenance (6, 7). Rev-erb␣ and Rev-erb␤ also regulate the expression of genes involved in gluconeogenesis, lipid homeostasis, and immune responses, ultimately synchronizing these processes to the diurnal cycle (16 -21).The multiple functions of NRs (DNA, ligand, and coregulator binding) are accomplished through their modular structure (22, 23). The N-terminal A/B domain is hypervariable, is involved in ligand-independent transcriptional regulation, and is subject to ...

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Modulation of nuclear receptor function by cellular redox poise

Cited by 21 publications

References 184 publications

Cellular Timekeeping: It’s Redox o’Clock

Cellular Timekeeping: It’s Redox o’Clock

Spatial perspectives in the redox code—Mass spectrometric proteomics studies of moonlighting proteins

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

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