Endoplasmic reticulum-resident selenoproteins as regulators of calcium signaling and homeostasis

Highlights

• Seven of twenty-five selenoproteins are localized to the ER with diverse structural features and different topologies.

• Some ER selenoproteins have been shown to be involved in sensing and regulating redox tone.

• Some ER selenoproteins regulate protein folding and the chaperoning of misfolded proteins during unfolded protein response.

• Some ER selenoproteins regulate Ca²⁺ flux and homeostasis.

• The role of the selenocysteine (Sec) residue in ER selenoproteins in some cases involves its oxidoreductase potential.

Abstract

The human selenoprotein family contains 25 members that share the common feature of containing the amino acid, selenocysteine (Sec). Seven selenoproteins are localized to the endoplasmic reticulum (ER) and exhibit different structural features contributing to a range of cellular functions. Some of these functions are either directly or indirectly related to calcium (Ca²⁺) flux or homeostasis. The presence of the unique Sec residue within these proteins allows some to exert oxidoreductase activity, while the function of the Sec in other ER selenoproteins remains unclear. Some functional insight has been achieved by identifying domains within the ER selenoproteins or through the identification of binding partners. For example, selenoproteins K and N (SELENOK AND SELENON) have been characterized through interactions detected with the inositol 1,4,5-triphosphate receptors (IP3Rs) and the SERCA2b pump, respectively. Others have been linked to chaperone functions related to ER stress or Ca²⁺ homeostasis. This review summarizes the details gathered to date regarding the ER-resident selenoproteins and their effect on Ca²⁺ regulated pathways and outcomes in cells.

Introduction

Selenium is an essential micronutrient that plays an important role in several aspects of human health. Deficient intake of selenium can lead to a wide variety of health disorders ranging from impaired gestational development, poor immunity, cognitive and neurodegenerative problems, and endocrine imbalances [1]. The biological effects of selenium are exerted mainly through the actions of selenoproteins, which contain this element in the form of the 21st amino acid selenocysteine (Sec) [2]. There are 25 selenoproteins in humans [3] that exhibit a wide range of biological functions with nearly half of the members still uncharacterized in terms of their function. Animal models have demonstrated the essential role of selenoproteins, as mice deficient in tRNA^Sec, the selenocysteine-specific tRNA required for selenoprotein synthesis, do not survive early embryogenesis [4]. The most studied selenoproteins include those that function as enzymes. The significance of these enzymes and other members of the selenoprotein family to human health have been demonstrated in patients with errors in the synthesis process or in the selenoproteins themselves [5]. A number of studies in humans have found that defects in expression or function of selenoproteins can impinge upon a variety of physiological processes involving the muscular and skeletal systems, respiratory system, neurological system, and endocrine system. Perhaps the best example of how selenoproteins affect multiple systems is the syndrome in which there is defective production or function of one protein involved in selenoprotein synthesis, the SECIS binding protein 2 (SECISBP2). Mutations in SECISBP2 give rise to a spectrum of health problems depending on the patient and/or type of mutation present [6].

There are 25 genes encoding selenoproteins in humans that were revealed in a 2003 hallmark study by the Gladyshev laboratory following the completion of the human genome project [3]. While several new members of the family were identified in that study, some selenoproteins had already been characterized as redox regulating enzymes containing the Sec residue located within the catalytic site. The defining characteristic of selenoproteins is the presence of the 21st amino acid Sec, which itself has special properties. The Sec residue is isosteric to cysteine (Cys) with selenium in place of sulfur. This results in a highly reactive site in the enzyme that is better at nucleophilic exchange reactions compared to Cys [7]. The lower pKa of the selenol side chain of Sec compared to thiol of Cys means that Sec is mostly deprotonated at physiological pH [8], and this further enhances its oxidoreductase activity.

Subsequent to the complete identification of the selenoprotein family members in 2003, the nomenclature was recently revised [9]. Selenoprotein enzymes with known functions are designated according to these functions. These include the glutathione peroxidases (GPXs), the thioredoxin reductases (TXNRDs), iodothyronine deiodinases (DIOs), methionine-R-sulfoxide reductase 1 (MSRB2) and selenophosphate synthetase 2 (SEPHS2). Those selenoproteins without a clearly demonstrated enzymatic function are named with the root symbol SELENO followed by a letter. A list of selenoproteins with the characteristics of each is shown in Table 1. As indicated in this table, several selenoproteins have been associated with a cellular function involving Ca²⁺, either directly or indirectly, and the remainder of this review will elaborate on ER-resident selenproteins and what is known regarding their Ca²⁺ relevant functions.