Selenophosphate synthetase 1 is an essential protein with roles in regulation of redox homoeostasis in mammals

Abstract

Selenophosphate synthetase (SPS) was initially detected in bacteria and was shown to synthesize selenophosphate, the active selenium donor. However, mammals have two SPS paralogs, which are designated SPS1 and SPS2. Although it is known that SPS2 catalyzes the synthesis of selenophosphate, the function of SPS1 remains largely unclear. To examine the role of SPS1 in mammals, we generated a Sps1 knockout mouse and found that systemic SPS1 deficiency led to embryos that were clearly underdeveloped by E8.5 and virtually resorbed by E14.5. The knockout of Sps1 in the liver preserved viability, but significantly affected the expression of a large number of mRNAs involved in cancer, embryonic development, and the glutathione system. Particularly notable was the extreme deficiency of glutaredoxin 1 (GLRX1) and glutathione-S-transferase omega 1. To assess these phenotypes at the cellular level, we targeted the removal of SPS1 in F9 cells, a mouse embryonal carcinoma cell line, which affected the glutathione system proteins and accordingly led to the accumulation of hydrogen peroxide in the cell. Further, we found that several malignant characteristics of SPS1-deficient F9 cells were reversed, suggesting that SPS1 played a role in supporting and/or sustaining cancer. In addition, the overexpression of mouse or human GLRX1 led to a reversal of observed increases in reactive oxygen species (ROS) in the F9 SPS1/GLRX1-deficient cells and resulted in levels that were similar to those in F9 SPS1-sufficient cells. The results suggested that SPS1 is an essential mammalian enzyme with roles in regulating redox homeostasis and controlling cell growth.

Cell competition corrects noisy Wnt morphogen gradients to achieve robust patterning in the zebrafish embryo

“…5e), are also involved in ROS-mediated apoptosis 25 . RNA-Seq data also showed that negative regulators of ROS ( aplnrb , hsp70.3 , sephs1 and dkc1 ) 26–29 were downregulated in unfit cells, whereas positive regulators ( fabp3 , ptgdsb.1 and krt8 ) 30–32 were upregulated (Fig. 5a and Supplementary Fig.…”

“…6). Co-expression of the ROS negative regulators SOD1 33 or Sephs1 29 , or smad4 knockdown reduced ROS and DNA-oxidization levels in β-catCA-expressing cells (Fig. 6b, c).…”

A Genetic Screen Using theDrosophila melanogasterTRiP RNAi Collection To Identify Metabolic Enzymes Required for Eye Development

“…Selenide water dikinase ( SelD ; FBgn0261270; BDSC 29553) encodes a member of the selenophosphate synthetase 1 (SPS1) enzyme family that does not synthesize selenophosphate but rather functions in redox homeostasis and glutathione metabolism (Xu et al 2007a; Xu et al 2007b; Tobe et al 2016). Consistent with the proposed functions of SPS1 proteins, SelD serves a critical role in Drosophila eye development by restricting reactive oxygen species (ROS) accumulation (Morey et al 2003).…”

Trypanosomatid selenophosphate synthetase structure, function and interaction with selenocysteine lyase

“…brucei ER stress. On the other hand, it is also possible that the only selenophosphate synthetase isoform observed in trypanosomatids ( Tb SPSH2) has a more direct role in redox homeostasis in the cell as suggested for the mammalian SEPHS1 [ 69 ].…”