editorial and special issue
Frontiers Research Topic "Redox Regulation and Signaling in Neurodegenerative Diseases"
can be accessed
here.
Oxidants and Redox Signaling: Perspectives in Cancer Therapy, Inflammation, and Plasma Medicine.
Bekeschus S, Bräutigam L, Wende K, Hanschmann EM. Oxid Med Cell Longev. 2017
PhD thesis
Thioredoxin family proteins in physiology and disease
Summary:
Proteins of the thioredoxin (Trx) family are ubiquitously expressed oxidoreductases. They use cysteinyl residues within their active site to modify substrate proteins posttranslationally by reduction/oxidation reactions or de-/glutathionylation. They play a crucial role in regulating cellular functions such as proliferation, differentiation and apoptosis. This thesis entitled “Thioredoxin family proteins in physiology and disease” focusses on these proteins, i.e. the Trx systems, the glutaredoxin (Grx) systems and the peroxiredoxins (Prxs). Because descriptions of cellular functions of redoxins are rare, we aimed at identifying new interaction partners and functions under physiological and hypoxic conditions in various cell culture and animal models.
We described the mitochondrial Grx2 as novel electron donor for Prx3, using a 2-Cys Prx-specific redox blot. Silencing the expression of Trx2, before this thesis the only known electron donor, or Grx2 in HeLa cells did not increase the level of oxidised Prx3, but simultaneous silencing did. Prx3 distribution in mouse tissues, was linked to the expression of either Trx2 or Grx2, depending on the cell type. Knock-down of Trx1 and Grx2 affected iron regulation in HeLa cells. Especially Grx3 depletion resulted in strong defects in iron homeostasis, impairing cytosolic and mitochondrial heme- and iron-sulfur cluster containing proteins in HeLa cells and hemoglobin maturation in zebrafish. Trx family proteins showed a tissue- and cell type-specific expression and distribution in the rat CNS and responded tissue- and cell type-specific to oxygen deprivation in numerous cell lines and models for perinatal asphyxia, renal ischemia/reperfusion (I/R) injury and transplantation of pancreatic ß-cells. Perinatal asphyxia in rat pups led to an immediate increase in the expression of Grx2, Trx1 and Trx2 four hours after induction of hypoxia. No significant longterm changes after 7 days were determined. Renal I/R injury led to segment-specific alterations in the distribution and expression of Trx family proteins in the ischemic kidney, but also to systemic effects in the contralateral kidney. In proximal tubule cells, which can regenerate after an I/R insult, levels of Grx2, Prx3 and Prx6 were upregulated. Overexpression of these proteins in HEK293 cells had a positive impact on cell proliferation and survival under hypoxic conditions. The protein levels of many cytosolic members of the Trx family were decreased, while the levels of mitochondrial proteins were increased in mouse models of pancreatic ß-cell transplantation. Trx1 was secreted during hypoxia and reduced macrophage migration, potentially preventing the initiation of the immune response. Overexpression of Trx1 and Trx2 enhanced cell proliferation and survival following hypoxia/reoxygenation, by affecting the phosphorylation pattern of the MAP kinases ERK, JNK and p38.
This thesis emphasizes the concept of compartmentalised redox signaling and demonstrates not only the complexity of the Trx family proteins, but the species-, tissue- and cell-type specific responses to oxygen deprivation and the distinct contribution of the redoxins to controling the fate of a cell.
PhD thesis
Thioredoxin family proteins in physiology and disease
Summary:
Proteins of the thioredoxin (Trx) family are ubiquitously expressed oxidoreductases. They use cysteinyl residues within their active site to modify substrate proteins posttranslationally by reduction/oxidation reactions or de-/glutathionylation. They play a crucial role in regulating cellular functions such as proliferation, differentiation and apoptosis. This thesis entitled “Thioredoxin family proteins in physiology and disease” focusses on these proteins, i.e. the Trx systems, the glutaredoxin (Grx) systems and the peroxiredoxins (Prxs). Because descriptions of cellular functions of redoxins are rare, we aimed at identifying new interaction partners and functions under physiological and hypoxic conditions in various cell culture and animal models. This thesis emphasizes the concept of compartmentalised redox signaling and demonstrates not only the complexity of the Trx family proteins, but the species-, tissue- and cell type-specific responses to oxygen deprivation and the distinct contribution of the redoxins to controling the fate of a cell. In detail: - Human, mitochondrial Grx2 is an electron donor for Prx3. - Vertebrate Grx3 (human and zebrafish) is involved in iron regulation. - Trx family proteins showed a tissue- and cell type-specific expression and distribution in the rat CNS and responded tissue- and cell type-specific to oxygen deprivation in numerous cell lines and models for perinatal asphyxia, renal ischemia/reperfusion (I/R) injury and transplantation of pancreatic β-cells. (compare to summary of the thesis).
Funding
The financial support, provided by the Deutsche Forschungsgemeinschaft
(SPP1710) and the Federation of European Biochemical Societies
is highly acknowledged.
To learn more about the SPP1710 on "Dynamics of Thiol-based Redox Switches in Cellular Physiology", visit
thiolswitches.de.