Affinage

SELENOT

Thioredoxin reductase-like selenoprotein T · UniProt P62341

Length
195 aa
Mass
22.3 kDa
Annotated
2026-06-10
13 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SELENOT is an ER-membrane-resident thioredoxin-like selenoprotein that couples redox catalysis to ER Ca2+ homeostasis, thereby integrating oxidative balance with Ca2+-dependent signaling across neuronal, endocrine, cardiac, and muscle tissues (PMID:17503775, PMID:40195499). It belongs to the Rdx thioredoxin-like family, bearing a conserved catalytic CxxU (selenocysteine) motif whose redox-active selenocysteine is required for function: a selenocysteine-containing peptide derived from its active site (PSELT) confers protection against oxidative and lipotoxic stress, whereas an inactive peptide lacking selenocysteine does not (PMID:17503775, PMID:37048116). Mechanistically, SELENOT binds SERCA2 at the ER membrane — but not IP3R or RyR — to govern ER-to-cytosol Ca2+ flux (PMID:40195499), and downstream of this Ca2+ control it tunes distinct effectors in different cells: NURR1 activity and dopamine transporter expression in dopaminergic neurons (PMID:40195499), CaMKII phosphorylation during myoblast differentiation (PMID:40085303), and MLCK activation with MLC phosphorylation driving smooth muscle contraction (PMID:26779623). SELENOT supports mitochondrial respiration, biogenesis, and dynamics and protects against mtROS-driven cell death, with its deficiency producing OXPHOS impairment, NADPH dysregulation, and disulfidptosis in skeletal muscle (PMID:37048116, PMID:40953299). Its expression is induced by PACAP/cAMP through an LKB1→AMPK→PGC-1α/NRF-1 cascade and is post-transcriptionally repressed by miR-365-3p, which directly targets SelT mRNA (PMID:30267375, PMID:38109331). Loss-of-function in vivo links SELENOT to catecholaminergic neuron density, ADHD-like behavior, and gonadotrope-axis (LH/GnRH) regulation, establishing it as a redox effector of neuroendocrine physiology (PMID:35066506, PMID:40195499, PMID:41196650).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 Medium

    Established SELENOT as a member of a novel thioredoxin-like (Rdx) selenoprotein family with a catalytic CxxU motif, framing it as a redox enzyme rather than a structural protein.

    Evidence Sequence similarity searches, GFP-fusion subcellular localization, and affinity pull-down with mutant proteins

    PMID:17503775

    Open questions at the time
    • Redox catalytic activity inferred by homology rather than measured biochemically
    • No physiological substrate identified
    • Localization shown by overexpressed GFP fusions only
  2. 2016 Medium

    Connected SELENOT to ER Ca2+ release and contractile signaling, the first functional readout linking it to Ca2+ control.

    Evidence siRNA knockdown in rat gastric smooth muscle with Ca2+, MLCK activity, and MLC phosphorylation assays

    PMID:26779623

    Open questions at the time
    • Molecular intermediary between SELENOT and Ca2+ channels not identified
    • Single tissue and single lab
    • Did not distinguish direct versus indirect effects on Ca2+ stores
  3. 2018 Medium

    Defined how SELENOT expression is driven, placing it downstream of PACAP/cAMP via a mitochondrial-biogenesis transcriptional cascade.

    Evidence Pharmacological/genetic manipulation of LKB1/AMPK/PGC-1α/NRF-1 in PC12 cells with survival and differentiation assays

    PMID:30267375

    Open questions at the time
    • Direct promoter occupancy by NRF-1 not demonstrated
    • Limited to one neuroendocrine cell line
  4. 2020 Medium

    Showed the redox active site is the functional unit by demonstrating a cell-permeable active-site peptide is neuroprotective, with a proposed nuclear EZH2-linked transcriptional output.

    Evidence PSELT peptide treatment of dopaminergic neurons, rodent PD models, transcriptomics, and behavior

    PMID:33486153

    Open questions at the time
    • EZH2 stimulation inferred from transcriptomics rather than direct biochemical assay
    • Mechanism of peptide entry and multi-compartment action unresolved
  5. 2022 Medium

    Demonstrated SELENOT maintains ER Ca2+ storage and modulates apoptotic balance under ER stress, reinforcing an ER-protective role.

    Evidence siRNA knockdown in A-172 glioblastoma cells with Ca2+ imaging, apoptosis assays, and stress challenge (MSA/SeNPs)

    PMID:35741332

    Open questions at the time
    • No direct binding partner mediating ER Ca2+ storage identified
    • Context-dependent apoptosis effects not mechanistically resolved
  6. 2022 Medium

    Provided in vivo evidence that SELENOT is required for normal catecholaminergic neuron density, linking the gene to brain neurochemistry.

    Evidence Brain-specific conditional knockout mice with IHC, RNAscope, and 3D light-sheet imaging of TH+ neurons

    PMID:35066506

    Open questions at the time
    • No molecular mechanism for neuron loss identified
    • Cell-autonomous versus circuit effects not separated
  7. 2023 Medium

    Established the redox-active selenocysteine as essential for mitochondrial protection against lipotoxicity in cardiomyocytes and identified CD36-dependent downregulation.

    Evidence siRNA knockdown plus active versus Sec-lacking peptide in H9c2 cells, Seahorse respirometry, TEM, and FTIR

    PMID:37048116

    Open questions at the time
    • Direct mitochondrial substrates of SELENOT not defined
    • Mechanism coupling ER-membrane SELENOT to mitochondrial dynamics unresolved
  8. 2023 Medium

    Identified miR-365-3p as a direct repressor of SelT mRNA, linking selenium deficiency to SELENOT loss and mitochondrial dysfunction in muscle.

    Evidence miR-365-3p gain/loss and SelT rescue in primary chicken myoblasts with mtROS, OXPHOS, ATP assays and embryo models

    PMID:38109331

    Open questions at the time
    • Direct miRNA-target binding site validation in mammals not shown
    • Avian model; conservation of regulation untested
  9. 2025 High

    Resolved the molecular basis of SELENOT's Ca2+ control by identifying SERCA2 as a direct ER-membrane partner that channels Ca2+ flux to NURR1/DAT and dopaminergic behavior.

    Evidence Cell-type-specific conditional KO mice, Co-IP of SELENOT with SERCA2 (negative controls IP3R/RyR), electrophysiology, EEG, and pharmacological rescue

    PMID:40195499

    Open questions at the time
    • Whether SELENOT redox-modifies SERCA2 directly not established
    • Reciprocal/structural validation of the interaction not shown
    • Single lab
  10. 2025 Medium

    Extended SELENOT's neuroendocrine role to the gonadotrope axis, positioning it as a redox effector of GnRH neuron activity controlling LH secretion.

    Evidence Brain-specific conditional KO mice with LH pulse monitoring, endocrine/histological analysis, and GnRH antagonist rescue

    PMID:41196650

    Open questions at the time
    • Molecular mechanism of redox regulation of GnRH neurons unresolved
    • Sex-specific phenotypes not mechanistically explained
  11. 2025 Medium

    Mapped a SELENOT/mtROS/NADPH axis governing disulfidptosis and muscle atrophy, connecting redox function to a defined cell-death modality.

    Evidence SelT knockdown/overexpression in myotubes and broiler models with mtROS, NADPH, Seahorse, actin disulfide assays, and pharmacological rescue (TEMPO, rotenone, BAY-876)

    PMID:40953299

    Open questions at the time
    • Direct enzymatic link between SELENOT and NADPH/cysteine metabolism not defined
    • Avian model
  12. 2025 Medium

    Confirmed SELENOT-dependent ER Ca2+ content drives CaMKII signaling during myoblast differentiation, generalizing the Ca2+-effector logic to muscle.

    Evidence SelT siRNA/overexpression in chicken myoblasts with CaMKII inhibitor (KN-93), ER Ca2+ measurement, and miR-365-3p manipulation

    PMID:40085303

    Open questions at the time
    • Whether SERCA2 mediates the ER Ca2+ effect in myoblasts not tested
    • Avian model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SELENOT's selenocysteine redox chemistry mechanistically couples to SERCA2-dependent Ca2+ handling and to mitochondrial/NADPH metabolism remains undefined.
  • No identified protein substrate of the CxxU catalytic site
  • No structural model of the SELENOT–SERCA2 interaction
  • Conservation of miR-365-3p regulation in mammals untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016209 antioxidant activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-162582 Signal Transduction 2
Partners
SERCA2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 SELENOT (SelT) belongs to a novel thioredoxin-like protein family (Rdx) possessing a conserved CxxU (selenocysteine) motif and proposed thioredoxin-like fold, suggesting a redox function via catalytic Sec forming transient mixed disulfides with substrate proteins. GFP fusion experiments showed distinct subcellular localization patterns in transfected cells. Sequence similarity searches, GFP fusion localization in transfected cells, affinity column pull-down with mutant versions of proteins Biochemistry Medium 17503775
2016 SELENOT regulates Ca2+ release from the ER, MLCK activation, and MLC phosphorylation in gastric smooth muscle, thereby controlling smooth muscle contraction. RNAi knockdown of SelT reduced Ca2+ release, MLCK activation, and MLC phosphorylation. RNA interference (siRNA knockdown of SelT), Western blot, qPCR, MLCK activity assay ([γ-32P]ATP incorporation), Ca2+ concentration measurement in rat gastric smooth muscle Biological trace element research Medium 26779623
2018 PACAP/cAMP-stimulated SELENOT gene transcription during neuroendocrine differentiation proceeds via a LKB1→AMPK→PGC-1α/NRF-1 transcriptional cascade, linking mitochondrial biogenesis signaling to antioxidant SELENOT expression and enabling neuroendocrine cell survival and differentiation. Pharmacological and genetic manipulation of AMPK/LKB1/PGC-1α/NRF-1 pathway in PC12 cells; PACAP/cAMP stimulation; gene expression analysis; cell survival and differentiation assays Molecular neurobiology Medium 30267375
2020 A peptide (PSELT) derived from the SELENOT redox active site is cell-permeable, acts in multiple subcellular compartments of dopaminergic neurons, and mechanistically stimulates the transcription factor EZH2 in the nucleus to confer neuroprotection against oxidative stress. Cell-penetrating peptide treatment of dopaminergic neurons, rodent PD models (neurotoxin), transcriptomic analysis, immunofluorescence, behavioral assays Redox biology Medium 33486153
2022 SELENOT knockdown in A-172 glioblastoma cells causes ER stress, reduces ER Ca2+ storage capacity, and suppresses expression of pro-apoptotic proteins (reducing baseline apoptosis). Under exogenous ER stress (MSA or SeNPs), SELENOT-deficient cells exhibit enhanced pro-apoptotic signaling through suppression of selenium-containing antioxidant proteins. siRNA knockdown of SELENOT, RT-qPCR, Western blot, Ca2+ imaging, apoptosis assays in A-172 cells Biology Medium 35741332
2022 Brain-specific SELENOT knockout mice show reduced numbers of tyrosine hydroxylase (TH)-positive catecholaminergic neurons in specific brain regions (area postrema, A11, zona incerta, hypothalamus), demonstrating SELENOT is required for normal catecholaminergic neuron density in the mouse brain. Brain-specific conditional knockout mice, immunohistochemistry, RNAscope in situ hybridization, 3D light-sheet imaging with iDISCO+ clearing, semi-automated quantification of TH+ neurons Neuroendocrinology Medium 35066506
2023 SELENOT localizes to the ER membrane in cardiomyocytes and regulates mitochondrial respiration, biogenesis, and dynamics (PGC-1α, DRP-1, OPA-1). Its redox-active selenocysteine is required for protection against lipotoxicity; an inert peptide lacking selenocysteine is non-protective. PA-induced downregulation of SELENOT occurs via CD36/FAT fatty acid transporter, and SELENOT deficiency exacerbates palmitate-induced cell death. siRNA knockdown of SELENOT in H9c2 cardiomyocytes, PSELT peptide treatment vs. inactive control (I-PSELT lacking Sec), mitochondrial respiration (Seahorse), TEM ultrastructural analysis, immunofluorescence, FTIR spectroscopy, Western blot Cells Medium 37048116
2023 miR-365-3p directly targets SelT mRNA to suppress its expression, linking Se deficiency to impaired mitochondrial function (mitochondrial superoxide accumulation, disrupted OXPHOS, reduced ATP production), cell cycle arrest, reduced myoblast proliferation, and increased apoptosis in chicken skeletal muscle. miR-365-3p overexpression/inhibition, SelT knockdown/overexpression in primary chicken myoblasts, mitochondrial ROS assay (Mito-TEMPO rescue), OXPHOS and ATP assays, omics analysis, chicken embryo models Journal of agricultural and food chemistry Medium 38109331
2025 SELENOT in dopaminergic neurons interacts with SERCA2 of the ER membrane (but not IP3R or RyR) to regulate ER-to-cytosol Ca2+ flux, which in turn controls the activity of transcription factor NURR1 and the expression levels of dopamine transporter (DAT). Loss of SELENOT in dopaminergic neurons reduces DAT expression, elevates extrasynaptic dopamine, and produces ADHD-like behaviors in male mice. Conditional knockout mice (dopaminergic neuron-specific, astrocyte-specific, whole-brain), Co-immunoprecipitation of SELENOT with SERCA2/IP3R/RYR, behavioral assays, electrophysiology (sEPSC), EEG, dopamine metabolite measurements, pharmacological rescue (amphetamine, methylphenidate) The EMBO journal High 40195499
2025 SELENOT deficiency in the brain impairs LH pulse secretion and elevates GnRH expression, leading to LH excess, elevated steroid hormones in males, and a PCOS-like phenotype in females, with restoration after GnRH antagonist administration. This identifies SELENOT as a redox effector of GnRH neuron activity controlling the gonadotrope axis. Brain-specific SELENOT conditional knockout mice, biochemical and histological analysis of gonadotrope axis, LH pulse monitoring, GnRH antagonist pharmacological rescue, fertility and sexual behavior assays JCI insight Medium 41196650
2025 In chicken skeletal muscle, SELENOT deficiency caused by Se deficiency impairs mitochondrial respiratory chain function, leading to mtROS overproduction, glucose metabolism reprogramming, NADPH dysregulation, cysteine accumulation, and disulfidptosis (abnormal actin disulfide bonding and muscle atrophy). TEMPO-mediated mtROS inhibition or NADPH supplementation partially rescues muscle atrophy, and SELENOT overexpression reverses these effects; rotenone-induced mtROS or BAY-876-mediated NADPH inhibition blocks SELENOT-mediated protection. SELENOT knockdown/overexpression in myotubes, SELENOT-deficient broiler models, mtROS assay, NADPH measurement, Seahorse metabolic analysis, actin disulfide bonding assay, pharmacological rescue experiments (TEMPO, rotenone, BAY-876) Advanced science Medium 40953299
2025 SelT mediates Ca2+ homeostasis in myoblasts: SelT deletion reduces ER Ca2+ content, suppresses CaMKII phosphorylation (p-CaMKII), and impairs myotube formation/myoblast differentiation. SelT overexpression promotes myotube growth via CaMKII activation, which is blocked by the CaMKII inhibitor KN-93. miR-365-3p targets SelT mRNA to inhibit myoblast differentiation via Ca2+ homeostasis disruption. SelT siRNA knockdown and pCDNA-SelT overexpression in primary chicken myoblasts, CaMKII inhibitor (KN-93) pharmacological block, ER Ca2+ content measurement, MHC abundance assay, miR-365-3p manipulation, chicken embryo model Biological trace element research Medium 40085303

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 SelT, SelW, SelH, and Rdx12: genomics and molecular insights into the functions of selenoproteins of a novel thioredoxin-like family. Biochemistry 164 17503775
2020 Cell-penetrating, antioxidant SELENOT mimetic protects dopaminergic neurons and ameliorates motor dysfunction in Parkinson's disease animal models. Redox biology 27 33486153
2018 AMPK Activation of PGC-1α/NRF-1-Dependent SELENOT Gene Transcription Promotes PACAP-Induced Neuroendocrine Cell Differentiation Through Tolerance to Oxidative Stress. Molecular neurobiology 26 30267375
2022 The Role of Selenoproteins SELENOM and SELENOT in the Regulation of Apoptosis, ER Stress, and Calcium Homeostasis in the A-172 Human Glioblastoma Cell Line. Biology 22 35741332
2025 Redox Cascade in Chicken Skeletal Muscle: SELENOT Suppression in Selenium Deficiency Triggers Disulfidptosis via mtROS-NADPH Dysregulation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 17 40953299
2023 Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State. Cells 17 37048116
2023 Low-Se Diet Increased Mitochondrial ROS to Suppress Myoblasts Proliferation and Promote Apoptosis in Broilers via miR-365-3p/SelT Signaling Axis. Journal of agricultural and food chemistry 12 38109331
2016 Se Enhances MLCK Activation by Regulating Selenoprotein T (SelT) in the Gastric Smooth Muscle of Rats. Biological trace element research 10 26779623
2015 Effects of Se on the Diversity of SelT Synthesis and Distribution in Different Smooth Muscle Tissues in Rats. Biological trace element research 7 26280902
2025 The selenocysteine-containing protein SELENOT maintains dopamine signaling in the midbrain to protect mice from hyperactivity disorder. The EMBO journal 4 40195499
2022 SELENOT Deficiency in the Mouse Brain Impacts Catecholaminergic Neuron Density: An Immunohistochemical, in situ Hybridization and 3D Light-Sheet Imaging Study. Neuroendocrinology 4 35066506
2025 Low Selenium Diet Inhibited CaMKII Activation via miR-365-3p/SelT Signaling Axis, Resulting in Myoblast Differentiation Disorders and Skeletal Muscle Damage in Broilers. Biological trace element research 1 40085303
2025 Central SELENOT deficiency impairs gonadotrope axis function, sexual behavior, and fertility in male and female mice. JCI insight 0 41196650

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