Thioredoxin (Trx) family proteins are key players in redox signaling. Here, we have analyzed glutaredoxin (Grx) 1 and Grx2 in age-related macular degeneration (AMD) and in retinal pigment epithelial (ARPE-19) cells. We hypothesized that these redoxins regulate cellular functions and signaling circuits such as cell proliferation, Wnt signaling and VEGF release that have been correlated to the pathophysiology of AMD. ARPE-19 cells were transfected with specific siRNAs to silence the expression of Grx1 and Grx2 and were analyzed for proliferation/viability, migration capacity, fi-catenin activation, and VEGF release. An active site-mutated C-X-X-S Grx1 was utilized to trap interacting proteins present in ARPE-19 cell extracts. In both, AMD retinas and in ARPE-19 cells incubated under hypoxia/reoxygenation conditions, Grx1 showed an increased nuclear localization. Grx1-silenced ARPE-19 cells showed a significantly reduced prolifer-ation and migration rate. Our trapping approach showed that Grx1 interacts with fi-catenin in a dithiol-disulfide exchange reaction. Knock-down of Grx1 led to a reduction in both total and active fi-catenin levels. These findings add redox control to the regulatory mechanisms of fi-catenin signaling in the retinal pigment epithelium and open the door to novel therapeutic approaches in AMD that is currently treated with VEGF-inhibitors.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Ischemic diseases, among others, myocardial infarction (MI), are the leading causes of death worldwide. MI is associated with a high tissue damage due in part to the activation of the immune response and the generation of reactive oxygen species (ROS), both taking place mainly during the reperfusion phase, once the blood supply to the tissue is restored. In spite of the harmful effects of ischemia and reperfusion, some injured cells manage to survive by activating endogenous defense mechanisms. Thioredoxins (Trxs) and peroxiredoxins (Prxs) are recognized as key molecules in redox signaling, regulating oxidative post-translational modifications of proteins (Trxs) and cellular levels of hydrogen peroxide (Prxs). Based on the strong evidence for a role of interrupted redox signaling in ischemia-reperfusion pathologies, we believe that Trxs and Prxs are potential defense mechanisms upregulated during ischemia-reperfusion damage. Using immunohistochemistry and Western blot analysis, we investigated the expression pattern of Trx1, Trx reductase 1, Trx2, Prx1, and Prx2 in the heart of rats one week after MI or sham operation. Trx1, Prx1, and Prx2 were upregulated in the heart after MI. Trx1 showed the strongest immunostainings after MI and was detected not only in cardiomyocytes, but also in various immune cell populations infiltrating the infarcted area. Interestingly, Trx1 changed its classical cytosolic localization observed in sham operated animals and was translocated into the cell nucleus of cardiomyocytes after MI. Trx1 was also detected in the serum of animals two days after MI. Trx reductase 1 and mitochondrial Trx2 did not show any changes after MI. These findings point to a putative role of Trx1 in the defense against IR-induced tissue damage in the heart that may be important, for instance, for cell survival and the modulation of the immune response.

Thioredoxins (Trxs), glutaredoxins (Grxs), and peroxiredoxins (Prxs) have been characterized as electron donors, guards of the intracellular redox state, and antioxidants. Today, these redox catalysts are increasingly recognized for their specific role in redox signaling. The number of publications published on the functions of these proteins continues to increase exponentially. The field is experiencing an exciting transformation, from looking at a general redox homeostasis and the pathological oxidative stress model to realizing redox changes as a part of localized, rapid, specific, and reversible redox-regulated signaling events. This review summarizes the almost 50 years of research on these proteins, focusing primarily on data from vertebrates and mammals. The role of Trx fold proteins in redox signaling is discussed by looking at reaction mechanisms, reversible oxidative post-translational modifications of proteins, and characterized interaction partners. On the basis of this analysis, the specific regulatory functions are exemplified for the cellular processes of apoptosis, proliferation, and iron metabolism. The importance of Trxs, Grxs, and Prxs for human health is addressed in the second part of this review, that is, their potential impact and functions in different cell types, tissues, and various pathological conditions. Antioxid. Redox Signal. 19, 1539-1605.

Cellular functions and survival are dependent on a tightly controlled redox potential. Currently, an increasing amount of data supports the concept of local changes in the redox environment and specific redox signaling events controlling cell function. Specific protein thiol groups are the major targets of redox signaling and regulation. Thioredoxins and glutaredoxins catalyze reversible thiol-disulfide exchange reactions and are primary regulators of the protein thiol redox state. Here, we demonstrate that embryonic brain development depends on the enzymatic activity of glutaredoxin 2. Zebrafish with silenced expression of glutaredoxin 2 lost virtually all types of neurons by apoptotic cell death and the ability to develop an axonal scaffold. As demonstrated in zebrafish and in a human cellular model for neuronal differentiation, glutaredoxin 2 controls axonal outgrowth via thiol redox regulation of collapsin response mediator protein 2, a central component of the semaphorin pathway. This study provides an example of a specific thiol redox regulation essential for vertebrate embryonic development.

Background: Oxidoreductases of the thioredoxin family of proteins have been thoroughly studied in numerous cellular and animal models mimicking human diseases. Despite of their well documented role in various disease conditions, no systematic information on the presence of these proteins is available.Methods: Here, we have systematically analyzed the presence of some of the major constituents of the glutaredoxin (Grx)-, peroxiredoxin (Prx)-, and thioredoxin (Trx)-systems, i.e. Grx1, Grx2, Grx3 (TXNL-2/PICOT), Grx5, nucleoredoxin (Nrx), Prx1, Prx2, Prx3, Prx4, Prx5, Prx6, Trx1, thioredoxin reductase 1 (TrxR1),Trx2,TrxR2, and -gamma-glutamyl cysteine synthetase (gamma-GCS) in various tissues of the mouse using immunohistochemistry.Results: The identification of the Trx family proteins in the central nervous system, sensory organs, digestive system, lymphatic system, reproductive system, urinary system, respiratory system, endocrine system, skin, heart, and muscle revealed a number of significant differences between these proteins with respect to their distribution in these tissues.Conclusion: Our results imply more specific functions and interactions between the proteins of this family than previously assumed.General significance: Crucial functions of Trx family proteins have been demonstrated in various disease conditions. A detailed overview on their distribution in various tissues will be helpful to fully comprehend their potential role and the interactions of these proteins in the most thoroughly studied model for human diseases the laboratory mouse.This article is part of a Special Issue entitled Human and Murine Redox Protein Atlases. (C) 2010 Elsevier B.V. All rights reserved.