Structure–Function Relations, Physiological Roles, and Evolution of Mammalian ER-Resident Selenoproteins

Abstract

Selenium is an essential trace element in mammals. The major biological form of this micronutrient is the amino acid selenocysteine, which is present in the active sites of selenoenzymes. Seven of 25 mammalian selenoproteins have been identified as residents of the endoplasmic reticulum, including the 15-kDa selenoprotein, type 2 iodothyronine deiodinase and selenoproteins K, M, N, S, and T. Most of these proteins are poorly characterized. However, recent studies implicate some of them in quality control of protein folding in the ER, retrotranslocation of misfolded proteins from the ER to the cytosol, metabolism of the thyroid hormone, and regulation of calcium homeostasis. In addition, some of these proteins are involved in regulation of glucose metabolism and inflammation. This review discusses evolution and structure-function relations of the ER-resident selenoproteins and summarizes recent findings on these proteins, which reveal the emerging important role of selenium and selenoproteins in ER function.

Selenoprotein S-dependent Selenoprotein K Binding to p97(VCP) Protein Is Essential for Endoplasmic Reticulum-associated Degradation

“…It has recently been demonstrated that, during ERAD, p97(VCP) forms a complex with derlins, SelS, and E3 liagases that plays an important role in the extraction of misfolded proteins from the ER to the cytosol (12,16,17). The association of p97(VCP) with derlins depends on the SelS.…”

“…The association of p97(VCP) with derlins depends on the SelS. However, the association of Hrd1 with derlins occurs independently of SelS (16,17). gp78 and SelS recruit p97(VCP) to the ER membrane, which mediates the ERAD machinery.…”

“…Both SelS and SelK are involved in the ERAD complex and associate with p97(VCP) and derlins (12,24,25). It is well known that SelS functions in cell survival by regulating ER stress (17,26). Recent studies have suggested that SelK is also an ER stress-regulated protein and plays an important role in resisting ER stress-mediated apoptosis (27).…”

Selective up-regulation of human selenoproteins in response to oxidative stress

“…TR1 and TR2 are expressed ubiquitously in the cytoplasm and mitochondria, respectively, whereas TR3 is only detected in the testis in the nucleus or ER. Selenoproteins that are present in the ER have been shown recently to participate in protein folding with the assistance of ER chaperones and/or ER-associated degradation of misfolded proteins (27). Sps2 (selenophosphate synthetase 2) participates in selenocysteine tRNA biosynthesis and, therefore, controls selenoprotein expression.…”

“…In addition to thioredoxin, a vast range of small molecules can also be reduced by TRs and participate in its antioxidant function. In parallel, the ER-resident selenoproteins, which include SelS, SelK, Sel15, and SelM, have important functions in protein folding and the ER stress response (27). ROS can severely damage a variety of macromolecules, including proteins, lipids, and nucleic acids.…”