Elsevier

Redox Biology

Volume 15, May 2018, Pages 297-315
Redox Biology

Research Paper
Mapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin – Thioredoxin system. 1. Understanding commonalities and differences among cell types

https://doi.org/10.1016/j.redox.2017.12.008Get rights and content
Under a Creative Commons license
open access

Highlights

  • A simple model maps cells’ protein composition to responses to H2O2 supply.

  • Most human cell lines are predicted to show a similar response to H2O2.

  • This similarity is due to protein concentrations being correlated over cell lines.

  • The yeast is predicted to show a response that is distinct from human cells’.

  • Capacity for PrxSS reduction sets a threshold separating distinct signaling regimes.

Abstract

The system (PTTRS) formed by typical 2-Cys peroxiredoxins (Prx), thioredoxin (Trx), Trx reductase (TrxR), and sulfiredoxin (Srx) is central in antioxidant protection and redox signaling in the cytoplasm of eukaryotic cells. Understanding how the PTTRS integrates these functions requires tracing phenotypes to molecular properties, which is non-trivial. Here we analyze this problem based on a model that captures the PTTRS’ conserved features. We have mapped the conditions that generate each distinct response to H2O2 supply rates (vsup), and estimated the parameters for thirteen human cell types and for Saccharomyces cerevisiae. The resulting composition-to-phenotype map yielded the following experimentally testable predictions. The PTTRS permits many distinct responses including ultra-sensitivity and hysteresis. However, nearly all tumor cell lines showed a similar response characterized by limited Trx-S- depletion and a substantial but self-limited gradual accumulation of hyperoxidized Prx at high vsup. This similarity ensues from strong correlations between the TrxR, Srx and Prx activities over cell lines, which contribute to maintain the Prx-SS reduction capacity in slight excess over the maximal steady state Prx-SS production. In turn, in erythrocytes, hepatocytes and HepG2 cells high vsup depletes Trx-S- and oxidizes Prx mainly to Prx-SS. In all nucleated human cells the Prx-SS reduction capacity defined a threshold separating two different regimes. At sub-threshold vsup the cytoplasmic H2O2 concentration is determined by Prx, nM-range and spatially localized, whereas at supra-threshold vsup it is determined by much less active alternative sinks and μM-range throughout the cytoplasm. The yeast shows a distinct response where the Prx Tsa1 accumulates in sulfenate form at high vsup. This is mainly due to an exceptional stability of Tsa1's sulfenate. The implications of these findings for thiol redox regulation and cell physiology are discussed. All estimates were thoroughly documented and provided, together with analytical approximations for system properties, as a resource for quantitative redox biology.

Abbreviations

ASK1
apoptosis signal-regulating kinase 1
Cat
catalase
GSH
glutathione
GPx1
glutathione peroxidase 1
Grx
glutaredoxin
KEAP1
Kelch-like ECH-associated protein 1
NRF2
nuclear factor erythroid 2-related factor 2
Prx
typical 2-Cys peroxiredoxin
PTTRS
peroxiredoxin / thioredoxin / thioredoxin reductase system
Srx
sulfiredoxin
Trx
thioredoxin
TrxR
thioredoxin reductase

Keywords

Redox relays
Redox signaling
Thiol redox regulation
Quantitative redox biology
Systems design space methodology

Cited by (0)