Selenocysteine Machinery Primarily Supports TXNRD1 and GPX4 Functions and Together They Are Functionally Linked with SCD and PRDX6

Abstract

The human genome has 25 genes coding for selenocysteine (Sec)-containing proteins, whose synthesis is supported by specialized Sec machinery proteins. Here, we carried out an analysis of the co-essentiality network to identify functional partners of selenoproteins and Sec machinery. One outstanding cluster included all seven known Sec machinery proteins and two critical selenoproteins, GPX4 and TXNRD1. Additionally, these nine genes were further positively associated with PRDX6 and negatively with SCD, linking the latter two genes to the essential role of selenium. We analyzed the essentiality scores of gene knockouts in this cluster across one thousand cancer cell lines and found that Sec metabolism genes are strongly selective for a subset of primary tissues, suggesting that certain cancer cell lineages are particularly dependent on selenium. A separate outstanding cluster included selenophosphate synthetase SEPHS1, which was linked to a group of transcription factors, whereas the remaining selenoproteins were linked neither to these clusters nor among themselves. The data suggest that key components of Sec machinery have already been identified and that their primary role is to support the functions of GPX4 and TXNRD1, with further functional links to PRDX6 and SCD.

Use of Cells, Supplements, and Peptides as Therapeutic Strategies for Modulating Inflammation after Spinal Cord Injury: An Update

“…Nanoparticles in rats with SCI have a neuroprotective effect and accelerate neuronal function by controlling the inflammatory response [ 164 ]. The essentiality of the selenoproteins GPX4, thioredoxin reductase 1 (TXNRD1), and thioredoxin reductase 2 (TXNRD2) for the normal development and survival of neurons became well understood after studying the phenotypes of respective gene knockout mice, which resulted in failed embryonic development [ 165 ].…”

Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers

“…The TXNRD family of enzymes are known for maintaining redox homeostasis utilizing thioredoxin as substrate [ 95 ]. TXNRDs and their role in cancer have also been reviewed elsewhere [ 96 , 97 , 98 ].…”

“…TXNRD1 is a critical selenoprotein in cancer cells [ 95 ], and found to be overexpressed in several cancer types when compared to TXNRD2 and TXNRD3 [ 99 ]. Table 1 depicts the regulation of the TXNRD1 gene according to the type of cancer.…”

“…To that matter, a recent study evaluated the co-essentiality network of the selenoprotein synthesis machinery within 485 human cancer cell lines and revealed a tight cluster encompassing genes for the selenoprotein synthesis machinery and three selenoproteins, SEPHS2, GPX4 and TXNRD1, suggesting that the machinery functions in most cancer cells to support the production of these selenoproteins [ 95 ]. Se taken up by human cancer cells, therefore, should be mostly used to produce these three selenoproteins.…”

Side-by-side comparison of recombinant human glutathione peroxidases identifies overlapping substrate specificities for soluble hydroperoxides

“…While these short-lived compounds can act as important signalling molecules modulating redox-sensitive signalling cascades, too high concentration can have detrimental effects for the cell. To prevent damage caused by peroxide overload, they have to be eliminated which is mainly mediated by antioxidant enzymes [ 1 ]. There are several enzymes capable of peroxide reduction including catalase, peroxiredoxins, and glutathione peroxidases (GPXs) [ 2 ].…”