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Mapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin - Thioredoxin system. 1. Understanding commonalities and differences among cell types.
Redox Biol. 2018 05; 15:297-315.RB

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.

Authors+Show Affiliations

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; MIT-Portugal Program Bioengineering Systems Doctoral Program, Portugal.CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CQC, Department of Chemistry, University of Coimbra, Portugal. Electronic address: salvador@cnc.uc.pt.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29304480

Citation

Selvaggio, Gianluca, et al. "Mapping the Phenotypic Repertoire of the Cytoplasmic 2-Cys Peroxiredoxin - Thioredoxin System. 1. Understanding Commonalities and Differences Among Cell Types." Redox Biology, vol. 15, 2018, pp. 297-315.
Selvaggio G, Coelho PMBM, Salvador A. Mapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin - Thioredoxin system. 1. Understanding commonalities and differences among cell types. Redox Biol. 2018;15:297-315.
Selvaggio, G., Coelho, P. M. B. M., & Salvador, A. (2018). Mapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin - Thioredoxin system. 1. Understanding commonalities and differences among cell types. Redox Biology, 15, 297-315. https://doi.org/10.1016/j.redox.2017.12.008
Selvaggio G, Coelho PMBM, Salvador A. Mapping the Phenotypic Repertoire of the Cytoplasmic 2-Cys Peroxiredoxin - Thioredoxin System. 1. Understanding Commonalities and Differences Among Cell Types. Redox Biol. 2018;15:297-315. PubMed PMID: 29304480.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin - Thioredoxin system. 1. Understanding commonalities and differences among cell types. AU - Selvaggio,Gianluca, AU - Coelho,Pedro M B M, AU - Salvador,Armindo, Y1 - 2017/12/21/ PY - 2017/11/23/received PY - 2017/12/19/accepted PY - 2018/1/6/pubmed PY - 2018/10/12/medline PY - 2018/1/6/entrez KW - Quantitative redox biology KW - Redox relays KW - Redox signaling KW - Systems design space methodology KW - Thiol redox regulation SP - 297 EP - 315 JF - Redox biology JO - Redox Biol VL - 15 N2 - 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. SN - 2213-2317 UR - https://www.unboundmedicine.com/medline/citation/29304480/Mapping_the_phenotypic_repertoire_of_the_cytoplasmic_2_Cys_peroxiredoxin___Thioredoxin_system__1__Understanding_commonalities_and_differences_among_cell_types_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2317(17)30881-9 DB - PRIME DP - Unbound Medicine ER -