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Spatially localized redox relays allow sensitive site-specific hydrogen peroxide signaling

Authors: Griffith, M; Araújo, A; Travasso, R; Salvador, A

Ref.: Free Radic. Biol. Med. 208 (1), S29-S-30 (2023)

Abstract: Hydrogen peroxide is a key signaling agent in important physiological processes such as cell proliferation, inflammation, and apoptosis. However, how such a featureless molecule achieves sensitive and specific regulation remains poorly understood. At the cytosol of human cells, H2O2 signaling is spatially localized due to the high activity of the peroxiredoxin (Prdx)/thioredoxin (Trx) system. And it is partly mediated by redox relays whereby Prdx act as H2O2 receptors, being oxidized, and in turn oxidize other protein targets. We used reaction-diffusion models of the cytosolic Prdx1/2-Trx1 system that accounts for the differential kinetic parameters of human Prdx1 and Prdx2 to analyze how spatial localization contributes for signaling specificity and sensitivity. The results show: (i) Disulfide and sulfenic forms of both peroxiredoxins, and Trx1 disulfide are spatially localized, Prdx1 species being more so than Prdx2’s. (ii) Scaffold proteins (ScP) recruiting both Prdx and regulation targets to H2O2 supply sites can greatly improve redox relays’ H2O2 detection limits. (iii) The input dynamic range is mainly determined by the association constant between redox target and ScP, rather than by Prdxs’ kinetic properties, allowing substantial target oxidation with little overall Prdx oxidation. (iv) Site-specific ScP allow H2O2 released to the cytosol at distinct sites to independently regulate distinct genes and processes.

DOI: 10.1016/j.freeradbiomed.2023.10.067

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