Regulatory phenomena in the glutathione peroxidase superfamily.

Expression of glutathione peroxidases (GPxs) and the regulatory consequences of their action are reviewed. The selenium-containing GPXs 1-4 protect against oxidative challenge, inhibit inflammation and oxidant-induced regulated cell death. GPx1 and GPx4 dampen phosphorylation cascades predominantly via prevention of inactivation of phosphatases by H2O2 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 interleukin1-driven NF-κB 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 alternate substrate. A yeast 2-Cys GPx was reported to sense H2O2 for inducing an adaptive response.