Hydrogen peroxide sensing, signaling and regulation of transcription factors

Abstract

The regulatory mechanisms by which hydrogen peroxide (H ₂O ₂) modulates the activity of transcription factors in bacteria (OxyR and PerR), lower eukaryotes (Yap1, Maf1, Hsf1 and Msn2/4) and mammalian cells (AP-1, NRF2, CREB, HSF1, HIF-1, TP53, NF-κB, NOTCH, SP1 and SCREB-1) are reviewed. The complexity of regulatory networks increases throughout the phylogenetic tree, reaching a high level of complexity in mammalians. Multiple H ₂O ₂ sensors and pathways are triggered converging in the regulation of transcription factors at several levels: (1) synthesis of the transcription factor by upregulating transcription or increasing both mRNA stability and translation; (ii) stability of the transcription factor by decreasing its association with the ubiquitin E3 ligase complex or by inhibiting this complex; (iii) cytoplasm–nuclear traffic by exposing/masking nuclear localization signals, or by releasing the transcription factor from partners or from membrane anchors; and (iv) DNA binding and nuclear transactivation by modulating transcription factor affinity towards DNA, co-activators or repressors, and by targeting specific regions of chromatin to activate individual genes. We also discuss how H ₂O ₂ biological specificity results from diverse thiol protein sensors, with different reactivity of their sulfhydryl groups towards H ₂O ₂, being activated by different concentrations and times of exposure to H ₂O ₂. The specific regulation of local H ₂O ₂ concentrations is also crucial and results from H ₂O ₂ localized production and removal controlled by signals. Finally, we formulate equations to extract from typical experiments quantitative data concerning H ₂O ₂ reactivity with sensor molecules. Rate constants of 140 M ⁻¹ s ⁻¹ and ≥1.3 × 10 ³ M ⁻¹ s ⁻¹ were estimated, respectively, for the reaction of H ₂O ₂ with KEAP1 and with an unknown target that mediates NRF2 protein synthesis. In conclusion, the multitude of H ₂O ₂ targets and mechanisms provides an opportunity for highly specific effects on gene regulation that depend on the cell type and on signals received from the cellular microenvironment.

Highlights

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  Complexity of redox regulation increases along the phylogenetic tree.

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  Complex regulatory networks allow for a high degree of H ₂O ₂ biological plasticity.

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  H ₂O ₂ modulates gene expression at all steps from transcription to protein synthesis.

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  Fast response (s) is mediated by sensors with high H ₂O ₂ reactivity.

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  Low reactivity H ₂O ₂ sensors may mediate slow (h) or localized H ₂O ₂ responses.

Graphical Abstract