ReviewEndoplasmic reticulum-resident selenoproteins as regulators of calcium signaling and homeostasis
Graphical abstract
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 tRNASec, 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.
Section snippets
Calcium homeostasis and ER stress
Within the cell, cytosolic levels of free Ca2+ are kept low under baseline conditions by the synchronized action of a variety of channels, pumps, exchangers, and Ca2+-binding proteins. The endoplasmic reticulum (ER) represents the primary storage site for intracellular Ca2+, with concentrations reaching high micromolar levels in this organelle, whereas resting cytosolic concentrations typically range from 50 to 200 nM [10]. Seven of the twenty-five members of the selenoprotein family are
Regulation of Ca2+ signaling by ER-resident selenoproteins
Various ER-resident selenoproteins have been shown to modulate Ca2+ flux into and out of the ER lumen, promote protein folding, and respond to ER luminal redox status. The following section will review what is currently known regarding these individual selenoproteins and how they impact Ca2+-related processes such as proliferation, survival, and apoptosis. The structural and topological features of the seven ER-resident selenoproteins suggest diversity even within this subgroup (Fig. 1). How
Conclusions
Several selenoproteins are localized to the ER but exhibit diverse structural features and different topologies, with some found in the membrane and others in the lumen. This is consistent with the notion that they play different roles, which has been borne out by reports showing some to be involved in sensing and regulating redox tone, and others regulating protein folding and the chaperoning of misfolded proteins during UPR (Fig. 2). In some cases, roles have been demonstrated for ER
Acknowledgements
This work was supported by U.S. National Institutes of Health (NIH)National Institute of Allergy and Infectious Diseases Grant R01AI089999.
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