Selenoprotein T: An Essential Oxidoreductase Serving as a Guardian of Endoplasmic Reticulum Homeostasis

Pothion, Hugo; Jehan, Cédric; Tostivint, Hervé; Cartier, Dorthe; Bucharles, Christine; Falluel‐Morel, Anthony; Boukhzar, Loubna; Anouar, Youssef; Lihrmann, Isabelle

doi:10.1089/ars.2019.7931

Cited by 37 publications

(35 citation statements)

References 134 publications

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“…The Se status is known to affect NF-kB activity, and a reduced Se status will cause an up-regulation of a whole set of inflammation-relevant genes [143]. During NF-kB activation, and in response to other noxae, a number of intracellular stress-regulated selenoproteins are induced including essential components affecting ER quality control mechanisms like SELENOF, SELENON, SELENOS, SELENOT, or SELENOV [144][145][146][147][148]. Notably, SNPs in the promoter of SELENOS have directly been associated with IL-6, IL1ß, and tumor necrosis factor-alpha expression in human subjects [149].…”

Section: Selenium Status and Rheumatoid Arthritismentioning

confidence: 99%

“…Glutathione peroxidases 1, 2 (GPX1, 2) control intracellular peroxide tone [160] Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides, prevents ferroptosis [161] Iodothyronine deiodinases (DIO2, 3) regulate activity of innate immune cells [162] Methionine-R-sulfoxide reductase (MSRB1) reduces oxidized Met, affects F-actin formation [163] Selenoprotein H (SELENOH) controls redox-sensitive transcription and damage [164] Selenoprotein I (SELENOI) contributes to the biosynthesis of phospholipids [165] Selenoprotein K (SELENOK) affects Ca-signaling and activity of lymphocytes [166] Selenoprotein P (SELENOP) mediates hierarchical Se supply, indicates Se status [8] Selenoprotein S (SELENOS) controls quality of proteins synthesized in ER [149] Selenoprotein T (SELENOT) controls redox state and protein quality in ER [144] Selenophosphate Synthetase 2 (SEPHS2) controls selenoprotein biosynthesis rate [167] Selenoprotein 15 (SEP15, SELENOF) gatekeeper for ER exit of immunoglobulins [168] Thioredoxin reductases 1, 2 (TXNRD1, 2) regenerate thioredoxin, balance mitochondrial ROS [169] It is at present unknown which of these immune-relevant selenoproteins respond most sensitively to Se deficiency and constitute the rate-limiting factors for a dysfunctional immune system under low Se supply. Besides the selenoproteins that affect lymphocyte activity, migration, proliferation, survival, and interaction directly, a large number of selenoproteins is involved in quality control of newly synthesized proteins in the ER affecting correct protein folding and retrotranslocation of misfolded proteins into the cytosol for degradation [170].…”

Section: Immune Dysfunction In Se Deficiency-possible Molecular Mechanismsmentioning

confidence: 99%

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Selenium Deficiency Due to Diet, Pregnancy, Severe Illness, or COVID-19—A Preventable Trigger for Autoimmune Disease

Schomburg

2021

IJMS

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The trace element selenium (Se) is an essential part of the human diet; moreover, increased health risks have been observed with Se deficiency. A sufficiently high Se status is a prerequisite for adequate immune response, and preventable endemic diseases are known from areas with Se deficiency. Biomarkers of Se status decline strongly in pregnancy, severe illness, or COVID-19, reaching critically low concentrations. Notably, these conditions are associated with an increased risk for autoimmune disease (AID). Positive effects on the immune system are observed with Se supplementation in pregnancy, autoimmune thyroid disease, and recovery from severe illness. However, some studies reported null results; the database is small, and randomized trials are sparse. The current need for research on the link between AID and Se deficiency is particularly obvious for rheumatoid arthritis and type 1 diabetes mellitus. Despite these gaps in knowledge, it seems timely to realize that severe Se deficiency may trigger AID in susceptible subjects. Improved dietary choices or supplemental Se are efficient ways to avoid severe Se deficiency, thereby decreasing AID risk and improving disease course. A personalized approach is needed in clinics and during therapy, while population-wide measures should be considered for areas with habitual low Se intake. Finland has been adding Se to its food chain for more than 35 years—a wise and commendable decision, according to today’s knowledge. It is unfortunate that the health risks of Se deficiency are often neglected, while possible side effects of Se supplementation are exaggerated, leading to disregard for this safe and promising preventive and adjuvant treatment options. This is especially true in the follow-up situations of pregnancy, severe illness, or COVID-19, where massive Se deficiencies have developed and are associated with AID risk, long-lasting health impairments, and slow recovery.

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Section: Selenium Status and Rheumatoid Arthritismentioning

confidence: 99%

Section: Immune Dysfunction In Se Deficiency-possible Molecular Mechanismsmentioning

confidence: 99%

Selenium Deficiency Due to Diet, Pregnancy, Severe Illness, or COVID-19—A Preventable Trigger for Autoimmune Disease

Schomburg

2021

IJMS

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“…Selenoprotein T (SELENOT) is a member of the selenoprotein family, whose members are characterized by containing one or more selenocysteine residues, frequently in enzymatically active sites [ 29 ]. SELENOT is the most highly conserved selenoprotein throughout evolution [ 30 ], suggestive of an essential function, which is underscored by the early embryonic lethality of mice in which the selenot gene is constitutively disrupted [ 31 ]. SELENOT is one of 7 out of 25 human selenoproteins localized to the ER [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

Selenoprotein T Protects Endothelial Cells against Lipopolysaccharide-Induced Activation and Apoptosis

et al. 2021

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Sepsis is an exaggerated immune response upon infection with lipopolysaccharide (LPS) as the main causative agent. LPS-induced activation and apoptosis of endothelial cells (EC) can lead to organ dysfunction and finally organ failure. We previously demonstrated that the first twenty amino acids of the Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) are sufficient to inhibit EC apoptosis. To identify genes whose regulation by LPS is affected by this N-terminal APEX1 peptide, EC were transduced with an expression vector for the APEX1 peptide or an empty control vector and treated with LPS. Following RNA deep sequencing, genes upregulated in LPS-treated EC expressing the APEX1 peptide were identified bioinformatically. Selected candidates were validated by semi-quantitative real time PCR, a promising one was Selenoprotein T (SELENOT). For functional analyses, an expression vector for SELENOT was generated. To study the effect of SELENOT expression on LPS-induced EC activation and apoptosis, the SELENOT vector was transfected in EC. Immunostaining showed that SELENOT was expressed and localized in the ER. EC transfected with the SELENOT plasmid showed no activation and reduced apoptosis induced by LPS. SELENOT as well as APEX1(1-20) can protect EC against activation and apoptosis and could provide new therapeutic approaches in the treatment of sepsis.

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“…In addition to MAGT1 and TUSC3, another oxidoreductase, Selenoprotein T, has recently been found to associate with OST complexes containing STT3A [ 47 , 48 ]. Selenoprotein T is a selenocysteine-containing protein with a thioredoxin-like domain containing an active-site CXXU motif.…”

Section: Oxidoreductases In the Oligosaccharyltransferase Complexmentioning

confidence: 99%

Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD

Patel

Saad

Shenkman

et al. 2020

Cells

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N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place in the endoplasmic reticulum (ER). They are essential modifications that are required for membrane and secretory proteins to achieve their correct folding and native structure. Several oxidoreductases responsible for disulfide bond formation, isomerization, and reduction have been shown to form stable, functional complexes with enzymes and chaperones that are involved in the initial addition of an N-glycan and in folding and quality control of the glycoproteins. Some of these oxidoreductases are selenoproteins. Recent studies also implicate glycan machinery–oxidoreductase complexes in the recognition and processing of misfolded glycoproteins and their reduction and targeting to ER-associated degradation. This review focuses on the intriguing cooperation between the glycoprotein-specific cell machineries and ER oxidoreductases, and highlights open questions regarding the functions of many members of this large family.

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Selenoprotein T: An Essential Oxidoreductase Serving as a Guardian of Endoplasmic Reticulum Homeostasis

Cited by 37 publications

References 134 publications

Selenium Deficiency Due to Diet, Pregnancy, Severe Illness, or COVID-19—A Preventable Trigger for Autoimmune Disease

Selenium Deficiency Due to Diet, Pregnancy, Severe Illness, or COVID-19—A Preventable Trigger for Autoimmune Disease

Selenoprotein T Protects Endothelial Cells against Lipopolysaccharide-Induced Activation and Apoptosis

Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD

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