Peroxiredoxin 1 and its role in cell signaling

Abstract

Peroxiredoxins (Prdxs) are a family of small (22-27 kDa) nonseleno peroxidases currently known to possess six mammalian isoforms. Although their individual roles in cellular redox regulation and antioxidant protection are quite distinct, they all catalyze peroxide reduction of H(2)O(2), organic hydroperoxides and peroxynitrite. They are found to be expressed ubiquitously and in high levels, suggesting that they are both an ancient and important enzyme family. Prdxs can be divided into three major subclasses: typical 2-cysteine (2-Cys) Prdxs (Prdx1-4), atypical 2-Cys Prdx (Prdx 5) and 1-Cys Prdx (Prdx 6). Recent evidence suggests that 2-Cys peroxiredoxins are more than "just simple peroxidases". This hypothesis has been discussed elegantly in recent review articles, considering "over"-oxidation of the protonated thiolate peroxidatic cysteine and post-translational modification of Prdxs as processes initiating a mechanistic switch from peroxidase to chaperon function. The process of over-oxidation of the peroxidatic cysteine (C(P)) occurs during catalysis in the presence of thioredoxin (Trx), thus rendering the sulfenic moiety to sulfinic acid, which can be reduced by sulfiredoxin (Srx). However, further oxidation to sulfonic acid is believed to promote Prdx degradation or, as recently shown, the formation of oligomeric peroxidase-inactive chaperones with questionable H(2)O(2)-scavenging capacity. In the light of this and given that Prdx1 has recently been shown by us and by others to interact directly with signaling molecules, we will explore the possibility that H(2)O(2) regulates signaling in the cell in a temporal and spatial fashion via oxidizing Prdx1. Therefore, this review will focus on H(2)O(2) modulating cell signaling via Prdxs by discussing: (1) the activity of Prdxs towards H(2)O(2); (2) sub cellular localization and availability of other peroxidases, such as catalase or glutathione peroxidases; (3) the availability of Prdxs reducing systems, such as thioredoxin and sulfiredoxin and lastly, (4) Prdx1 interacting signaling molecules.

Figure 1.

Cellular H₂O₂ levels are controlled sequentially by peroxidases. Prdxs and Gpxs scavenge smaller amounts of H₂O₂ whereas catalase catalyses higher amounts. Small amounts of H₂O₂ result in glutathionylation of Cys-thiols 51, 82 and 172 in Prdx1, which can be deglutathionylated by Srx and Grx1. The disulfide structure comprising sulfenic Prdx1 Cys⁵¹ and Cys¹⁷² from another Prdx1 protein can be reduced by Trx, Trx-reductase and NADPH. Further elevation of H₂O₂ promotes oxidation of Prdx1 Cys⁵¹ sulfenic acid to sulfinic acid. This process is reversible through an ATP and Mg²⁺ dependent reduction reaction induced by Srx. Oxidation of sulfinic Prdx1 Cys⁵¹ to sulfonic acid however is not reversible. Such over-oxidized Prdx1 proteins tend to form decamers with questionable peroxidase activity, but protein chaperone function. Such functional switch from peroxidase to chaperon elevates in turn cellular H₂O₂, which is then scavenged by catalase. Compared to Prdxs, catalase is not readily over-oxidized and decomposes H₂O₂ following an exponential decay, since its rate of H₂O₂ decomposition depends linearly on H₂O₂ concentration.

Figure 2.

Prdx1 prevents Akt-driven tumorigenesis through protecting PTEN lipid phosphatase activity from oxidation-induced inactivation. (A) Prdx1 regulates PTEN phosphatase activity during oxidative stress, since binding of Prdx1 and PTEN occurs in conditions of mild or nil cellular stress. This constitutes a setting in which H₂O₂ is scavenged by Prdx1, which itself becomes in turn reversibly oxidized, in a controlled fashion. (B) However, under conditions of elevated oxidative stress, Prdxs are known to become irreversibly over-oxidized and dissociate from PTEN. Thereby, PTEN is inactivated by H₂O₂ resulting in hyperactivation of Akt. Hyperactive Akt then in turn can promote oncogenic signaling via ErbB-2- and Ras.