Role Of Selenoproteins Research Articles

The Regulation of Selenoproteins in Diabetes: A New Way to Treat Diabetes.

Selenium is an essential micronutrient required for the synthesis and function of selenoproteins, most of which are enzymes involved in maintaining oxidative balance in the body. Diabetes is a group of metabolic disorders characterized by high blood glucose levels over a prolonged period of time. There are three main types of diabetes: type 1, type 2, and gestational diabetes. This review summarizes recent advances in the field of diabetes research with an emphasis on the roles of selenoproteins on metabolic disturbance in diabetes. We also discuss the interaction between selenoproteins and glucose and lipid metabolism to provide new insights into the prevention and treatment of diabetes.

Role of Selenoprotein W in participating in the progression of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease worldwide. Numerous evidence has demonstrated that metabolic reprogramming serves as a hallmark associated with an elevated risk of NAFLD progression. Selenoprotein W (SelW) is an extensively expressed hepatic selenoprotein that plays a crucial role in antioxidant function. Here, we first demonstrated that SelW is a significantly distinct factor in the liver tissue of NAFLD patients through the Gene Expression Omnibus (GEO) database. Additionally, loss of SelW alleviated hepatic steatosis induced by a high-fat diet (HFD), and was accompanied by the regulation of metabolic and inflammatory pathways as verified by transcriptomic analysis. Moreover, co-immunoprecipitation (CO-IP), liquid chromatography-tandem mass spectrometry (LC-MS), laser scanning confocal microscopy (LSCM) and molecular docking analysis were subsequently implemented to identify Pyruvate Kinase M2 (PKM2) as a potential interacting protein of SelW. Meanwhile, SelW modulated PKM2 translocation into the nucleus to trigger transactivation of the HIF-1α, in further mediating mitochondrial apoptosis, eventually resulting in mitochondrial damage, ROS excessive production and mtDNA leakage. Additionally, mito-ROS accumulation induced the activation of the NLRP3 inflammasome-mediated pyroptosis, thereby facilitating extracellular leakage of mtDNA. The escaped mtDNA then evokes the cGAS-STING signaling pathway in macrophage, thus inducing a shift in macrophage phenotype. Together, our results suggest SelW promotes hepatocyte apoptosis and pyroptosis by regulating metabolic reprogramming to activate cGAS/STING signaling of macrophages, thereby exacerbating the progression of NAFLD.

Selenoprotein P concentrations and risk of progression from mild cognitive impairment to dementia

There is a growing literature investigating the effects of selenium on the central nervous system and cognitive function. However, little is known about the role of selenoprotein P, the main selenium transporter, which can also have adverse biological effects. We conducted a prospective cohort study of individuals aged 42–81 years who received a clinical diagnosis of mild cognitive impairment. Using sandwich ELISA methods, we measured full-length selenoprotein P concentrations in serum and cerebrospinal fluid to assess the relation with dementia incidence during a median follow-up of 47.3 months. We used Cox proportional hazards regression and restricted cubic splines to model such relation. Of the 54 participants, 35 developed dementia during follow-up (including 26 cases of Alzheimer’s dementia). Selenoprotein P concentrations in serum and cerebrospinal fluid were highly correlated, and in spline regression analyses they each showed a positive non-linear association with dementia risk, particularly after excluding dementia cases diagnosed within 24 months of follow-up. We also observed differences in association according to the dementia subtypes considered. Risk ratios of dementia peaked at 2–6 at the highest levels of selenoprotein P, when compared to its median level, also depending on matrix, analytical methodology and dementia subtype. Findings of this study, the first to assess selenoprotein P levels in the central nervous system in vivo and the first to use a prospective study design to evaluate associations with dementia, suggest that higher circulating concentrations of selenoprotein P, both in serum and cerebrospinal fluid, predict progression of MCI to dementia. However, further confirmation of these findings is required, given the limited statistical precision of the associations and the potential for residual confounding.

The role of selenoproteins in neurodevelopment and neurological function: Implications in autism spectrum disorder.

Selenium and selenoproteins play a role in many biological functions, particularly in brain development and function. This review outlines the role of each class of selenoprotein in human brain function. Most selenoproteins play a large antioxidant role within the brain. Autism spectrum disorder (ASD) has been shown to correlate with increased oxidative stress, and the presumption of selenoproteins as key players in ASD etiology are discussed. Further, current literature surrounding selenium in ASD and selenium supplementation studies are reviewed. Finally, perspectives are given for future directions of selenoprotein research in ASD.

The role of selenoprotein M in nickel-induced pyroptosis in mice spleen tissue via oxidative stress.

Nickel (Ni) is a heavy metal element and a pollutant that threatens the organism's health. Melatonin (Mel) is an antioxidant substance that can be secreted by the organism and has a protective effect against heavy metals. Selenoprotein M (SelM) is a selenoprotein widely distributed of the body, and its role is to protect these tissues from oxidative damage. To study the mechanism of Ni, Mel, and SelM in mouse spleen, 80 SelM+/+ wild-type and 80 SelM-/- homozygous mice were divided into 8 groups with 20 mice in each group. The Ni group was intragastric at a concentration of 10mg/kg, while the Mel group was intragastric at 2mg/kg. Mice were injected with 0.1mL/10g body weight for 21days. Histopathological and ultrastructural observations showed the changes in Ni, such as the destruction of white and red pulp and the appearance of pyroptosomes. SelM knockout showed more severe injury, while Mel could effectively interfere with Ni-induced spleen toxicity. The results of antioxidant capacity determination showed that Ni could cause oxidative stress in the spleen, and Mel could also effectively reduce oxidative stress. Finally, Ni exposure increased the expression levels of the pyroptotic genes, including apoptosis-associated speck protein (ASC), absent in melanoma-2 (AIM2), NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), Caspase-1, interleukin- (IL-) 18, and IL-1β (p < 0.05). Loss of SelM significantly increased these (p < 0.05), while Mel decreased the alleviated impact of Ni. In conclusion, the loss of SelM aggravated Ni-induced pyroptosis of the spleen via activating oxidative stress, which was alleviated by Mel, but the effect of Mel was not obvious in the absence of SelM, which reflected the important role of SelM in Ni-induced pyroptosis.

Roles of selenoprotein K in oxidative stress and endoplasmic reticulum stress under selenium deficiency in chicken liver

Selenoprotein K (SELENOK) is a major part of selenoprotein family. Selenoproteins have been proven playing vital roles in a variety of physiological processes. However, as a necessary supplement to the body of trace elements, how SELENOK regulates necroptosis in chicken liver has none clear claim. The purpose of this study was to cover the mechanism of SELENOK act in necroptosis of chicken liver. By feeding Se-deficiency diet for 1-day-old hyline chickens, we successfully built SELENOK-deficiency and discussed the regulation SELENOK have done. The test of liver function showed there has dysfunction appeared in the -Se groups. Results of TEM showed necroptosis occurred in the 35-Se group. After that western blot and qRT-PCR results prompted us SELENOK-deficiency caused large accumulation of ROS, enhanced endoplasmic reticulum stress, abnormally elevated HSPs family expression, and activated RIPK1-RIPK3 complex. In order to show the regulation of SELENOK in chicken liver, we artificially knocked off SELENOK gene in LMH cells. Through AO/EB staining we also found necroptosis in the siRNA-Se group. Furthermore, the results in LMH cells were coincided with those in chicken (Gallus gallus) liver. Our experiment clarified the molecular mechanism of SELENOK in the regulation and liver necroptosis, and provided reference for the healthy feeding mode of broilers.

Selenoprotein: Potential Player in Redox Regulation in Chlamydomonas reinhardtii.

Selenium (Se) is an essential micro-element for many organisms, including Chlamydomonas reinhardtii, and is required in trace amounts. It is obtained from the 21st amino acid selenocysteine (Sec, U), genetically encoded by the UGA codon. Proteins containing Sec are known as selenoproteins. In eukaryotes, selenoproteins are present in animals and algae, whereas fungi and higher plants lack them. The human genome contains 25 selenoproteins, most of which are involved in antioxidant defense activity, redox regulation, and redox signaling. In algae, 42 selenoprotein families were identified using various bioinformatics approaches, out of which C. reinhardtii is known to have 10 selenoprotein genes. However, the role of selenoproteins in Chlamydomonas is yet to be reported. Chlamydomonas selenoproteins contain conserved domains such as CVNVGC and GCUG, in the case of thioredoxin reductase, and CXXU in other selenoproteins. Interestingly, Sec amino acid residue is present in a catalytically active domain in Chlamydomonas selenoproteins, similar to human selenoproteins. Based on catalytical active sites and conserved domains present in Chlamydomonas selenoproteins, we suggest that Chlamydomonas selenoproteins could have a role in redox regulation and defense by acting as antioxidants in various physiological conditions.

The role of selenoprotein P in the determining the sensitivity of cervical cancer patients to concurrent chemoradiotherapy: A metabonomics-based analysis

BackgroundThe effect of selenoprotein P (SELENOP) levels on the sensitivity of cervical cancer patients to concurrent chemoradiotherapy (CCRT) has not been reported. In this study, the effects of the variations in plasma SELENOP levels on the sensitivity of cervical cancer patients to CCRT were investigated using metabonomics. MethodsTwo patient groups were evaluated, i.e., the case group: 11 patients with intermediate to advanced primary squamous cervical cancer, who developed resistance against CCRT, and the sensitivity group: 11 patients who did not develop resistance were matched in a 1:1 ratio (controls). Blood samples were collected before and after CCRT, and the plasma SELENOP levels were measured by ELISA. The different metabolites present in the plasma were analyzed by UPLC-MS-MS. ResultsSELENOP levels exhibited a significant reduction in both the resistant and sensitive groups after CCRT (F = 50.705, P < 0.001), and interaction effects between sensitivity and pre-and post-treatment on SELENOP levels were observed (F = 7.414, P = 0.013). Further, a more significant reduction in the SELENOP levels was observed in the CCRT-resistant group (mean reduction, 0.028 µg/mL; P < 0.001) than in the sensitive group (mean reduction, 0.013 µg/mL; P = 0.006). Four metabolic biomarkers, i.e., C18, C19, C20 sphingomyelin, and phosphatidylcholine 20:2/22:6, were shown to be differentially expressed between the resistant and sensitive groups pre-and post-treatment. C20 sphingomyelin levels exhibited a significant correlation with SELENOP levels (r = −0.326, P = 0.031). ConclusionThe levels of plasma SELENOP in the CCRT-resistant group decreased significantly, suggesting that SELENOP might affect the sensitivity by modulating lipid synthesis and metabolism.

Role of selenoprotein P expression in the function of pancreatic β cells: Prevention of ferroptosis-like cell death and stress-induced nascent granule degradation

Selenoprotein P (SELENOP) is a major selenium (Se)-containing protein (selenoprotein) in human plasma that is mainly synthesized in the liver. SELENOP transports Se to the cells, while SELENOP synthesized in peripheral tissues is incorporated in a paracrine/autocrine manner to maintain the levels of cellular selenoproteins, called the SELENOP cycle. Pancreatic β cells, responsible for the synthesis and secretion of insulin, are known to express SELENOP. Here, using MIN6 cells as a mouse model for pancreatic β cells and Selenop small interfering (si)RNA, we found that Selenop gene knockdown (KD) resulted in decreased cell viability, cellular pro/insulin levels, insulin secretion, and levels of several cellular selenoproteins, including glutathione peroxidase 4 (Gpx4) and selenoprotein K (Selenok). These dysfunctions induced by Selenop siRNA were recovered by the addition of Se. Ferroptosis-like cell death, regulated by Gpx4, was involved in the decrease of cell viability by Selenop KD, while stress-induced nascent granule degradation (SINGD), regulated by Selenok, was responsible for the decrease in proinsulin. SINGD was also observed in the pancreatic β cells of Selenop knockout mice. These findings indicate a significant role of SELENOP expression for the function of pancreatic β cells by maintaining the levels of cellular selenoproteins such as GPX4 and SELENOK.

Human Genetic Disorders Resulting in Systemic Selenoprotein Deficiency.

Selenium, a trace element fundamental to human health, is incorporated as the amino acid selenocysteine (Sec) into more than 25 proteins, referred to as selenoproteins. Human mutations in SECISBP2, SEPSECS and TRU-TCA1-1, three genes essential in the selenocysteine incorporation pathway, affect the expression of most if not all selenoproteins. Systemic selenoprotein deficiency results in a complex, multifactorial disorder, reflecting loss of selenoprotein function in specific tissues and/or long-term impaired selenoenzyme-mediated defence against oxidative and endoplasmic reticulum stress. SEPSECS mutations are associated with a predominantly neurological phenotype with progressive cerebello-cerebral atrophy. Selenoprotein deficiency due to SECISBP2 and TRU-TCA1-1 defects are characterized by abnormal circulating thyroid hormones due to lack of Sec-containing deiodinases, low serum selenium levels (low SELENOP, GPX3), with additional features (myopathy due to low SELENON; photosensitivity, hearing loss, increased adipose mass and function due to reduced antioxidant and endoplasmic reticulum stress defence) in SECISBP2 cases. Antioxidant therapy ameliorates oxidative damage in cells and tissues of patients, but its longer term benefits remain undefined. Ongoing surveillance of patients enables ascertainment of additional phenotypes which may provide further insights into the role of selenoproteins in human biological processes.

Female Mice with Selenocysteine tRNA Deletion in Agrp Neurons Maintain Leptin Sensitivity and Resist Weight Gain While on a High-Fat Diet.

The role of the essential trace element selenium in hypothalamic physiology has begun to come to light over recent years. Selenium is used to synthesize a family of proteins participating in redox reactions called selenoproteins, which contain a selenocysteine residue in place of a cysteine. Past studies have shown that disrupted selenoprotein expression in the hypothalamus can adversely impact energy homeostasis. There is also evidence that selenium supports leptin signaling in the hypothalamus by maintaining proper redox balance. In this study, we generated mice with conditional knockout of the selenocysteine tRNA[Ser]Sec gene (Trsp) in an orexigenic cell population called agouti-related peptide (Agrp)-positive neurons. We found that female TrspAgrpKO mice gain less weight while on a high-fat diet, which occurs due to changes in adipose tissue activity. Female TrspAgrpKO mice also retained hypothalamic sensitivity to leptin administration. Male mice were unaffected, however, highlighting the sexually dimorphic influence of selenium on neurobiology and energy homeostasis. These findings provide novel insight into the role of selenoproteins within a small yet heavily influential population of hypothalamic neurons.

Prospects for the use of synthetic organoselenium compounds for the correction of metabolic and immune status during vaccination with live attenuated vaccines against especially dangerous infections

This review article analyzes the data on the role of selenium in the regulation of the metabolic and immune status of a macroorganism. The data on endogenous functional selenium-containing molecules, which include selenocysteine, selenomethionine, and selenoproteins, are considered. The data on the pathologies associated with the deficiency of this microelement, its immunotropic properties and adjuvant effects are presented. The role of selenoproteins in the regulation of redox processes has been shown. The data on the immunotropic activity of compounds containing selenium and the prospects for their use as adjuvants are analyzed. The last section is devoted to the analysis of literature data on the biological properties of synthetic selenium compounds with an activity that mimics the catalytic activity of selenoproteins. The analysis of the data on the functional activity of selenoproteins carried out in this work indicates their key role in the regulation of metabolic and immune processes, as well as in maintaining homeostasis. The information presented in this review on the biological activity and mechanisms of action of new synthetic low-toxic organic compounds of selenium can serve as a basis for the development of nonspecific means of metabolic and immune correction of vaccinal processes caused by both live attenuated vaccines and artificially created ones.

Roles of selenoprotein S in reactive oxygen species-dependent neutrophil extracellular trap formation induced by selenium-deficient arteritis

Selenium (Se) deficiency and poor plasma Se levels can cause cardiovascular diseases by decreasing selenoprotein levels. Neutrophil extracellular traps (NETs) may be the vicious cycle center of inflammation in vasculitis. Here, we show that Se deficiency induced arteritis mainly by reducing selenoprotein S (SelS), and promoted the progression of arteritis by regulating the recruitment of neutrophils and NET formation. Silencing SelS induced chicken arterial endothelial cells (PAECs) to secrete cytokines, and activated neutrophils to promote NET formation. Conversely, scavenging DNA-NETs promoted cytokine secretion in PAECs. The NET formation regulated by siSelS was dependent on a reactive oxygen species (ROS) burst. We also found that the PPAR pathway was a major mediator of NET formation induced by Se-deficient arteritis. Overall, our results reveal how Se deficiency regulates NET formation in the progression of arteritis and support silencing-SelS worsens arteritis.

The role of human selenoprotein S in SARS‐CoV‐2 replication

COVID‐19, caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), spread quickly all over the world and caused a pandemic that urged the scientific community to study the virus. Selenoprotein S is an endoplasmic reticulum (ER) membrane associated selenoprotein that is involved in protein degradation and NFκβ signaling. It also contributes to reducing proinflammatory cytokines TNF‐α, IL‐1β and IL‐6. Selenoprotein S is known to interact with SARS‐CoV‐2 non‐structural protein (nsp7), which is part of the virus replication machine. However, it is not clear whether they interact directly and whether selenoprotein S can still bind nsp7 once it is in complex with the virus’ replication machinery. The role of selenoprotein S in the replication complex is unknown. We used biochemical assays to investigate these open questions and to identify which segment of selenoprotein S is involved in the interaction and which segment is free to recruit other human or viral proteins. We show that selenoprotein S binds tightly and directly to nsp7. Selenoprotein S is a membrane protein and its hydrophobic region is the main segment involved in binding nsp7. The soluble cytosolic segment cannot bind to nsp7. Therefore, it is free for binding to other protein partners. In addition, selenoprotein S was able to bind the nsp7 and nsp8 complex suggesting that it can bind the core replication complex directly. Thus, we suggest that selenoprotein S is a component of the virus core replication complex and may be responsible for recruiting other human proteins to the replication complex.

Chemopreventive and Anticancer Property of Selenoproteins in Obese Breast Cancer.

Obesity is a significant risk factor for various cancers including breast cancer resulting in an increased risk of recurrence as well as morbidity and mortality. Extensive studies on various pathways have been successful in establishing a biological relationship between obesity and breast cancer. The molecular classification of breast cancer includes five groups each having different responses to treatment. Increased levels of inflammatory cytokines seen in obese conditions drive the pro-proliferative pathways, such as the influx of macrophages, angiogenesis, and antiapoptotic pathways. Increased peripheral aromatization of androgens by aromatase increases the circulating estrogen levels which are also responsible for the association of obesity with breast cancer. Also, increased oxidative stress due to chronic low-grade inflammation in obese women plays an important role in carcinogenesis. Despite the availability of safe and effective treatment options for breast cancer, obese women are at increased risk of adverse outcomes including treatment-related toxicities. In the recent decade, selenium compounds have gained substantial interest as chemopreventive and anticancer agents. The chemical derivatives of selenium include inorganic and organic compounds that exhibit pro-oxidant properties and alter cellular redox homeostasis. They target more than one metabolic pathway by thiol modifications, induction of reactive oxygen species, and chromatin modifications to exert their chemopreventive and anticancer activities. The primary functional effectors of selenium that play a significant role in human homeostasis are selenoproteins like glutathione peroxidase, thioredoxin reductase, iodothyronine deiodinases, and selenoprotein P. Selenoproteins play a significant role in adipose tissue physiology by modulating preadipocyte proliferation and adipogenic differentiation. They correlate negatively with body mass index resulting in increased oxidative stress that may lead to carcinogenesis in obese individuals. Methylseleninic acid effectively suppresses aromatase activation thus reducing the estrogen levels and acting as a breast cancer chemopreventive agent. Adipose-derived inflammatory mediators influence the selenium metabolites and affect the proliferation and metastatic properties of cancer cells. Recently selenium nanoparticles have shown potent anticancer activity which may lead to a major breakthrough in the management of cancers caused due to multiple pathways. In this review, we discuss the possible role of selenoproteins as chemopreventive and an anticancer agent in obese breast cancer.

Roles of Selenoproteins in Brain Function and the Potential Mechanism of Selenium in Alzheimer's Disease.

Selenium (Se) and its compounds have been reported to have great potential in the prevention and treatment of Alzheimer’s disease (AD). However, little is known about the functional mechanism of Se in these processes, limiting its further clinical application. Se exerts its biological functions mainly through selenoproteins, which play vital roles in maintaining optimal brain function. Therefore, selenoproteins, especially brain function-associated selenoproteins, may be involved in the pathogenesis of AD. Here, we analyze the expression and distribution of 25 selenoproteins in the brain and summarize the relationships between selenoproteins and brain function by reviewing recent literature and information contained in relevant databases to identify selenoproteins (GPX4, SELENOP, SELENOK, SELENOT, GPX1, SELENOM, SELENOS, and SELENOW) that are highly expressed specifically in AD-related brain regions and closely associated with brain function. Finally, the potential functions of these selenoproteins in AD are discussed, for example, the function of GPX4 in ferroptosis and the effects of the endoplasmic reticulum (ER)-resident protein SELENOK on Ca2+ homeostasis and receptor-mediated synaptic functions. This review discusses selenoproteins that are closely associated with brain function and the relevant pathways of their involvement in AD pathology to provide new directions for research on the mechanism of Se in AD.

Interplay between Oxidative Stress and Metabolic Derangements in Non-Alcoholic Fatty Liver Disease: The Role of Selenoprotein P.

Background: Pathogenetic mechanisms involved in the progression of non-alcoholic fatty liver disease (NAFLD) are complex and multifactorial. We investigated oxidative stress through the measurement of selenoprotein P (SeP) in serum and we explored its relation to metabolic derangements and liver damage in a group of non-diabetic NAFLD subjects. Methods: 57 NAFLD patients underwent a double-tracer oral glucose tolerance test (OGTT). Insulin resistance (IR) components were calculated at baseline as follows: hepatic-IR = (endogenous glucose production*insulin); peripheral-IR = (glucose rate of disappearance(Rd)); adipose-tissue(AT)-IR as Lipo-IR = (glycerol rate of appearance (Ra)*insulin) or AT-IR = (free fatty acids (FFAs)*insulin). The lipid and amino acid (AA) profiles were assessed by gas chromatography–mass spectrometry. SeP levels were measured by enzyme immunosorbent assay. Results: Circulating SeP correlated with insulin (rS = 0.28), FFAs (rS = 0.42), glucose Rd (rS = −0.33) and glycerol Ra (rS = −0.34); consistently, SeP levels correlated with Lipo-IR and AT-IR (rS > 0.4). Among the AA and lipid profiles, SeP inversely correlated with serine (rS = −0.31), glycine (rS = −0.44) and branched chain AA (rS = −0.32), and directly correlated with saturated (rS = 0.41) and monounsaturated FFAs (rS = 0.40). Hepatic steatosis and fibrosis increased in subjects with higher levels of SeP. In multivariable regression analysis, SeP was associated with the degree of hepatic fibrosis (t = 2.4, p = 0.022). Conclusions: SeP levels were associated with an altered metabolic profile and to the degree of hepatic fibrosis, suggesting a role in the pathogenesis of NAFLD.

SeP is elevated in NAFLD and participates in NAFLD pathogenesis through AMPK/ACC pathway.

Nonalcoholic fatty liver disease (NAFLD) is prevalent chronic liver diseases with unknown mechanism and no curative treatment. Hepatokines have demonstrated importance in NAFLD but, role of selenoprotein P (SeP) in NAFLD is unknown. A total of 79 patients with NAFLD and 79 healthy controls were included in this case-control study. SeP is elevated in patients with NAFLD. With elevating level of SeP, NAFLD prevalence, and detecting rate increases. As NAFLD aggravated, serum SeP increases. Correlation analysis demonstrates that SeP is positively associated with NAFLD risk factors including body mass index, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, and serum uric acid. Both NAFLD in vivo and in vitro models, SeP protein level is higher in liver. Small interfering RNA of SEPP1 inhibited TG accumulation by activating adenosine monophosphate activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC), and overexpression of SEPP1 aggravated lipid accumulation and inhibited AMPK/ACC phosphorylation. SeP expression is activated in NAFLD and exacerbated NAFLD through AMPK/ACC, providing insight into new diagnostic, therapeutic target in NAFLD.

Roles of selenoprotein T and transglutaminase in active immunization against entomopathogenic fungi in the termite Reticulitermes chinensis

Active immunization can protect individuals from infectious diseases in social insects. It is well established that trace elements are essential to the host immune system, but the related gene functions in insect social immunity are unknown. Here, we found that the levels of three free elements (Se, Ca and Cr) and selenoprotein T (SELT) expression were significantly decreased in the termite Reticulitermes chinensis Snyder during active immunization against the entomopathogenic fungus Metarhizium anisopliae (Metchnikoff) Sorokin. Thus, we further explored the role of the SELT gene in the active immunization of termites. After SELT was significantly silenced by RNAi, the nestmates of fungus-contaminated termites exhibited reduced antifungal activity and increased mortality, along with increased expression of the immune genes transglutaminase (TG) and transferrin (Tsf), indicating that the active immunization of termites was disrupted by SELT silencing. Moreover, the TG-knockdown nestmates of fungus-contaminated termites significantly decreased grooming behavior, antifungal activity and survival, despite the upregulation of SELT expression, also suggesting that the active immunization of termites was disrupted by the silencing of TG. These findings demonstrated that both SELT gene and TG gene play important roles in driving active immunization against the entomopathogenic fungus M. anisopliae in R. chinensis.

Human Disorders Affecting the Selenocysteine Incorporation Pathway Cause Systemic Selenoprotein Deficiency.

Significance: Generalized selenoprotein deficiency has been associated with mutations in SECISBP2, SEPSECS, and TRU-TCA1-1, 3 factors that are crucial for incorporation of the amino acid selenocysteine (Sec) into at least 25 human selenoproteins. SECISBP2 and TRU-TCA1-1 defects are characterized by a multisystem phenotype due to deficiencies of antioxidant and tissue-specific selenoproteins, together with abnormal thyroid hormone levels reflecting impaired hormone metabolism by deiodinase selenoenzymes. SEPSECS mutations are associated with a predominantly neurological phenotype with progressive cerebello-cerebral atrophy. Recent Advances: The recent identification of individuals with defects in genes encoding components of the selenocysteine insertion pathway has delineated complex and multisystem disorders, reflecting a lack of selenoproteins in specific tissues, oxidative damage due to lack of oxidoreductase-active selenoproteins and other pathways whose nature is unclear. Critical Issues: Abnormal thyroid hormone metabolism in patients can be corrected by triiodothyronine (T3) treatment. No specific therapies for other phenotypes (muscular dystrophy, male infertility, hearing loss, neurodegeneration) exist as yet, but their severity often requires supportive medical intervention. Future Directions: These disorders provide unique insights into the role of selenoproteins in humans. The long-term consequences of reduced cellular antioxidant capacity remain unknown, and future surveillance of patients may reveal time-dependent phenotypes (e.g., neoplasia, aging) or consequences of deficiency of selenoproteins whose function remains to be elucidated. The role of antioxidant therapies requires evaluation. Antioxid. Redox Signal. 33, 481-497.