Regulatory Phenomena in the Glutathione Peroxidase Superfamily

Abstract

Significance: The selenium-containing Glutathione peroxidases (GPxs)1-4 protect against oxidative challenge, inhibit inflammation and oxidant-induced regulated cell death. Recent Advances: GPx1 and GPx4 dampen phosphorylation cascades predominantly via prevention of inactivation of phosphatases by H 2 O 2 or lipid hydroperoxides. GPx2 regulates the balance between regeneration and apoptotic cell shedding in the intestine. It inhibits inflammation-induced carcinogenesis in the gut but promotes growth of established cancers. GPx3 deficiency facilitates platelet aggregation likely via disinhibition of thromboxane biosynthesis. It is also considered a tumor suppressor. GPx4 is expressed in three different forms. The cytosolic form proved to inhibit interleukin-1-driven nuclear factor jB activation and leukotriene biosynthesis. Moreover, it is a key regulator of ferroptosis, because it reduces hydroperoxy groups of complex lipids and silences lipoxygenases. By alternate substrate use, the nuclear form contributes to chromatin compaction. Mitochondrial GPx4 forms the mitochondrial sheath of spermatozoa and, thus, guarantees male fertility. Out of the less characterized GPxs, the cysteine-containing GPx7 and GPx8 are unique in contributing to oxidative protein folding in the endoplasmic reticulum by reacting with protein isomerase as an alternate substrate. A yeast 2-Cysteine glutathione peroxidase equipped with CP and CR was reported to sense H 2 O 2 for inducing an adaptive response. Critical Issues: Most of the findings compiled are derived from tissue culture and/or animal studies only. Their impact on human physiology is sometimes questionable. Future Directions: The expression of individual GPxs and GPx-dependent regulatory phenomena are to be further investigated, in particular in respect to human health. Antioxid. Redox Signal. 33, 498-516.

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

“…It is still debated if oxidants such as H 2 O 2 directly oxidize these signaling proteins, or if enzymes such as peroxiredoxins act as redox relays (reviewed in [84]). Nonetheless, antioxidant enzymes, including the GPx family members, are important regulators of these signaling cascades by manipulating levels of oxidants at cellular redox signaling hubs [28,85]. We highlight several studies in Section 3.2 where GPx3 has been implicated in modulating the activity of redox signaling pathways in cancer cells [32,[86][87][88][89][90].…”

Proteotoxic Stress and Cell Death in Cancer Cells

“…For example, glutathione peroxidases can regulate ferroptosis through their ability to reduce hydroperoxy groups in complex lipids and to silence lipoxygenases. However, they can also play a part during the oxidative protein-folding control in ER by reacting with protein isomerase as an alternate substrate [173].…”

Selenium and Selenoproteins in Adipose Tissue Physiology and Obesity

“…Generally, GPX-specific reaction is reduction of H2O2 and other hydroperoxide using reduced glutathione (GSH) as thiol donor [35]. Therefore, physiological role of GPXs is mediated by its involvement in redox regulation of cellular functions [36]. In human, GPX1, GPX2, GPX3, GPX4, and GPX6 are the Se-containing GPX isoforms and characterized by different localizations in cytoplasm, intestine, plasma, cytoplasm/mitochondria/nucleus and embryos/adult olfactory epithelium, respectively, whereas GPX4 plays a role of phospholipid hydroperoxide.…”