Affinage

Showing SELENOS — VIMP is a alias.

SELENOS

Selenoprotein S · UniProt Q9BQE4

Length
189 aa
Mass
21.2 kDa
Annotated
2026-06-10
33 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SELENOS (SelS/SEPS1) is an endoplasmic reticulum-associated selenoprotein that links ER homeostasis to cellular redox balance, inflammation, and stress-induced apoptosis (PMID:15063746, PMID:19398551). Its expression is induced by glucose deprivation and pharmacological ER stress in parallel with GRP78, marking it as a glucose-regulated, stress-responsive protein (PMID:15063746). In the face of ER stress, SELENOS acts protectively: it lowers active ATF6, suppresses GRP78 promoter activity and NF-κB signaling to dampen the unfolded protein and ER overload responses (PMID:19398551), and its loss sensitizes macrophages, astrocytes, and muscle cells to ER stress-induced death (PMID:17210132, PMID:18498015, PMID:42025965). SELENOS possesses oxidoreductase activity that modulates reactive oxygen species, and its inactive, selenocysteine-lacking truncated form is targeted for proteasomal degradation by the Cul5-type ubiquitin ligase KLHDC1 (PMID:32200094). Through this antioxidant and ER-protective role it restrains inflammatory mediator production—ROS, NO, iNOS, SAA1, TNF-α and IL-6—partly by inhibiting p38 MAPK signaling (PMID:18675776, PMID:24573439). SELENOS participates in a bidirectional positive feedback loop with the Nrf2 antioxidant program (PMID:31426718), and in metabolic settings is transcriptionally driven by HSF1 to activate an XBP1s/PPARγ lipogenic axis (PMID:35248747). A secreted form of SELENOS is detectable in serum and associates with LDL/VLDL fractions (PMID:17374524).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 Medium

    Established SELENOS as a stress-responsive gene by showing it is induced under glucose deprivation and ER stress and that its overexpression buffers cells against oxidative toxicity, framing it as a redox-protective ER protein.

    Evidence ER stress inducer treatment, Western blot, and overexpression viability assay in HepG2 and Min6 cells

    PMID:15063746

    Open questions at the time
    • No molecular activity defined
    • Mechanism of redox protection not resolved
  2. 2007 Medium

    Defined SELENOS as a survival factor specifically against ER stress-induced apoptosis using bidirectional perturbation, and separately showed it can be secreted and lipoprotein-associated, raising an extracellular dimension.

    Evidence Overexpression and siRNA in RAW264.7 macrophages; Brefeldin A/cycloheximide secretion blockade, ELISA, and serum fractionation in hepatoma cells

    PMID:17210132 PMID:17374524

    Open questions at the time
    • Function of the secreted form unknown
    • Pro-survival molecular mechanism not defined
  3. 2008 Medium

    Showed SELENOS restrains inflammatory mediator output and protects against ischemic stress, extending its role from cell survival to inflammation control via its antioxidant/ERAD-associated activity.

    Evidence siRNA knockdown with ROS/NO/iNOS/SAA1/GPx readouts in HepG2; differential display and siRNA in an OGD astrocyte injury model

    PMID:18498015 PMID:18675776

    Open questions at the time
    • Direct enzymatic activity not demonstrated
    • Causal chain from SELENOS loss to inflammatory output indirect
  4. 2009 Medium

    Provided mechanistic detail on ER stress suppression by showing SELENOS lowers active ATF6, GRP78 promoter activity, and NF-κB signaling, defining a chaperone-like dampening of the UPR/ER overload response.

    Evidence Overexpression with reporter assays, ATF6 Western blot, and NF-κB activity assay in a ZAAT-induced ER stress model in HepG2

    PMID:19398551

    Open questions at the time
    • Whether effects are direct or downstream not resolved
    • No structural basis for chaperone-like action
  5. 2010 Medium

    Confirmed the anti-apoptotic role under chemically induced ER stress and tied it to selenium status, reinforcing SELENOS as a protective node in the ER stress-apoptosis axis.

    Evidence siRNA knockdown and selenite supplementation with apoptosis and GRP78 readouts in HepG2

    PMID:20114070

    Open questions at the time
    • Apoptotic effectors directly engaged not identified
  6. 2014 Medium

    Identified p38 MAPK as a signaling route through which SELENOS suppresses inflammatory cytokines in vivo, connecting its loss to systemic organ damage in sepsis.

    Evidence In vivo siRNA knockdown in an LPS-sepsis mouse model with p38 phosphorylation Western blot, cytokine ELISA, and organ damage markers

    PMID:24573439

    Open questions at the time
    • Direct link between SELENOS and p38 activation not established
    • Cell type responsible in vivo unclear
  7. 2018 Medium

    Demonstrated a cell-type-specific antioxidant function in muscle, where SELENOS knockdown elevates oxidative and ER stress in myoblasts but not differentiated myotubes.

    Evidence Two-construct siRNA knockdown with H2O2, GSH:GSSG, viability, and stress marker readouts in C2C12 myoblasts and myotubes

    PMID:30557449

    Open questions at the time
    • Basis for myoblast vs myotube difference unexplained
  8. 2019 Medium

    Placed SELENOS in a bidirectional positive feedback loop with the Nrf2 antioxidant transcription factor, with relevance to autoimmune thyroid disease.

    Evidence Nrf2 knockout mice, siRNA in PCCL3 thyroid cells, and Hashimoto's thyroiditis tissue IHC

    PMID:31426718

    Open questions at the time
    • Molecular mechanism of reciprocal regulation not defined
    • Direct vs indirect feedback unresolved
  9. 2020 High

    Provided the most rigorous mechanistic anchor by defining SELENOS as an oxidoreductase promoting ROS production and identifying KLHDC1 as the Cul5 ubiquitin ligase that degrades its inactive, selenocysteine-lacking truncated form.

    Evidence Co-IP ligase identification, KLHDC1 and SELENOS knockdown, proteasome inhibition, ROS and cell-death assays in U2OS cells

    PMID:32200094

    Open questions at the time
    • Substrate/partner of the oxidoreductase activity not identified
    • Structural basis of KLHDC1 recognition not resolved
  10. 2022 Medium

    Connected SELENOS to lipid metabolism by establishing an HSF1-SELENOS-IRE1α-XBP1s-PPARγ lipogenic axis responsive to selenium form.

    Evidence RNAi epistasis (SELENOS, PPARγ), ChIP for HSF1 promoter binding, and lipid measurements in yellow catfish liver

    PMID:35248747

    Open questions at the time
    • Conservation of axis in mammals not directly tested
    • Mechanism linking SELENOS to IRE1α activation unclear
  11. 2023 Medium

    Validated SELENOS as an antioxidant ROS suppressor in cancer, where its loss sensitizes colorectal cells to drug-induced, ROS-mediated killing in vivo.

    Evidence SELENOS knockdown with ROS, JNK/p38/ER stress signaling Western blot, and mouse xenograft in colorectal cancer cells

    PMID:37598924

    Open questions at the time
    • Direct enzymatic contribution to ROS levels not isolated
  12. 2026 Medium

    Reinforced SELENOS's role in muscle ER stress responses by showing its loss worsens ER stress-induced apoptosis and impairs myotube differentiation under heat stress.

    Evidence siRNA knockdown with ER stress and apoptosis marker panels and differentiation assays in C2C12 cells and myotubes

    PMID:42025965

    Open questions at the time
    • Apoptotic effector directly regulated not pinned down

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct molecular substrate of SELENOS oxidoreductase activity and its precise role within the ERAD retro-translocation machinery remain undefined.
  • No identified redox substrate
  • No structural model of SELENOS in the ERAD channel
  • Reconciliation of ROS-promoting (oxidoreductase) and ROS-suppressing (antioxidant) roles unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 1
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005576 extracellular region 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2
Partners
KLHDC1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 SELENOS (SelS) gene expression is upregulated by glucose deprivation and ER stress inducers (tunicamycin, thapsigargin) in HepG2 cells, in parallel with GRP78, identifying it as a novel glucose-regulated protein. Overexpression of SelS increased Min6 cell resistance to oxidative stress-induced toxicity, indicating a role in regulating cellular redox balance. Cell treatment with ER stress inducers, Western blot for protein levels, overexpression with viability assay FEBS letters Medium 15063746
2007 SEPS1 overexpression in RAW264.7 macrophages protects against ER stress-induced apoptosis and promotes cell survival; conversely, siRNA-mediated suppression of SEPS1 sensitizes macrophages to ER stress-induced cell death. The protective action is specifically dependent on ER stress-mediated cell death signaling. Overexpression studies, siRNA knockdown, cell viability/apoptosis assays with pharmacological ER stress agents Biochemical and biophysical research communications Medium 17210132
2007 SEPS1 protein is secreted from hepatoma cells via the ER-Golgi pathway (secretion abolished by Brefeldin A and cycloheximide). Secreted SEPS1 is detectable in human serum and associates with LDL and possibly VLDL fractions. Brefeldin A and cycloheximide inhibitor studies, sandwich ELISA, serum fractionation Biochemical and biophysical research communications Medium 17374524
2008 siRNA-mediated silencing of SelS in HepG2 cells aggravates LPS-induced increases in ROS, NO, iNOS activity, and SAA1 secretion, and further decreases GPx-1 activity. This implicates SelS as a negative regulator of inflammatory mediator production, likely through its role as a component of the ERAD retro-translocation channel and its antioxidative properties. siRNA knockdown, ROS measurement, NO/iNOS assay, RT-PCR, ELISA for SAA1, GPx activity assay Archives of biochemistry and biophysics Medium 18675776
2008 SEPS1 gene is induced in astrocytes by oxygen and glucose deprivation (OGD/ischemia model). siRNA knockdown of SEPS1 severely increases astrocyte injury caused by OGD, demonstrating that SEPS1 protects astrocytes against ischemia by modulating ER stress. RNA differential display, siRNA knockdown, OGD cell injury assay Journal of molecular neuroscience Medium 18498015
2009 SEPS1 overexpression in HepG2 cells reduces levels of active ATF6, inhibits GRP78 promoter activity, and suppresses NF-κB activity in the context of Z-variant alpha1-antitrypsin (ZAAT)-induced ER stress. Selenium supplementation enhances these effects, demonstrating a chaperone-like activity that decreases the unfolded protein response and ER overload response. Transfection/overexpression, GRP78 promoter-reporter assay, ATF6 Western blot, NF-κB activity assay, glutathione peroxidase activity assay The Journal of biological chemistry Medium 19398551
2010 siRNA-mediated silencing of SelS in HepG2 cells aggravates beta-mercaptoethanol-induced ER stress and cell apoptosis. Selenite pretreatment (which increases SelS expression) alleviates beta-ME-induced apoptosis, demonstrating that SelS protects cells from ER stress-induced apoptosis. siRNA knockdown, sodium selenite supplementation, apoptosis assay, Western blot for GRP78 Biochimica et biophysica acta Medium 20114070
2014 siRNA knockdown of SEPS1 in mice with LPS-induced sepsis increases TNF-α and IL-6 production, worsens organ damage (elevated ALT, AST, BUN, LDH, CK, CK-MB), and significantly activates p38 MAPK phosphorylation, indicating that SEPS1 suppresses inflammatory cytokine production partly by inhibiting the p38 MAPK pathway. In vivo siRNA knockdown in LPS-sepsis mouse model, Western blot for p38 MAPK phosphorylation, ELISA for cytokines, biochemical organ damage markers Molecular medicine reports Medium 24573439
2019 In Nrf2 knockout mice, SELENOS expression is reduced in thyroid follicular cells; conversely, siRNA-mediated reduction of SELENOS in PCCL3 rat thyroid cells reduces Nrf2 signaling activity. This bidirectional positive feedback between Nrf2 and SelS pathways was supported by immunohistochemistry showing reduced SelS in thyroid follicular cells of Hashimoto's thyroiditis patients. Nrf2 knockout mouse model, siRNA knockdown in thyroid cell line, immunohistochemistry, Nrf2 activity assay Thyroid Medium 31426718
2020 The Cul5-type ubiquitin ligase KLHDC1 targets truncated (Sec-lacking) SELENOS for proteasomal degradation. Truncated SELENOS lacks oxidoreductase activity and its accumulation (when KLHDC1 is knocked down) decreases ER stress-induced cell death; knockdown of SELENOS itself increases the proportion of cells with lower ROS levels. This establishes SELENOS as an oxidoreductase that promotes ROS production and that KLHDC1 eliminates its inactive truncated form. Co-IP/ubiquitin ligase identification, KLHDC1 knockdown in U2OS cells, proteasome inhibition, ROS measurement, cell death assay iScience High 32200094
2018 In C2C12 myoblasts, siRNA knockdown of Seps1 (~50–75%) exacerbates palmitate-induced oxidative and ER stress, decreasing cell viability and proliferation, increasing H2O2 levels, lowering the GSH:GSSG ratio, and enhancing ER and oxidative stress marker gene expression. Even without palmitate, Seps1 knockdown increased oxidative stress in myoblasts. In contrast, in differentiated myotubes, the same knockdown did not significantly enhance ER stress markers under palmitate treatment, demonstrating cell-type-specific antioxidant function. siRNA knockdown (two constructs), cell viability assay, H2O2 measurement, GSH:GSSG ratio, RT-PCR for stress markers Physiological reports Medium 30557449
2023 Regorafenib suppresses SELENOS expression in colorectal cancer cells, which promotes ROS production and activates ER stress, JNK, and p38 signaling pathways. SELENOS knockdown sensitizes cells to regorafenib-induced ROS-mediated anti-tumor effects, confirming SELENOS functions as an antioxidant suppressor of ROS in CRC cells. SELENOS knockdown, ROS measurement, Western blot for signaling pathway activation, mouse xenograft model European journal of pharmacology Medium 37598924
2022 In yellow catfish liver, dietary sodium selenite (vs. selenomethionine) increases HSF1 binding to the SELENOS promoter, upregulating SELENOS expression, which in turn activates the XBP1s/PPARγ pathway to promote lipogenesis. RNA interference of SELENOS or PPARγ abolished selenite-induced lipid accumulation, establishing the HSF1-SELENOS-IRE1α-XBP1s-PPARγ axis in lipid metabolism regulation. RNA interference (SELENOS and PPARγ), ChIP for HSF1 binding, Western blot, lipid/triglyceride measurement, enzyme activity assays Biochimica et biophysica acta. Gene regulatory mechanisms Medium 35248747
2026 SELENOS knockdown in C2C12 cells and myotubes exacerbates ER stress-induced apoptosis and impairs myotube differentiation under heat stress conditions, supporting a contributory role for SELENOS in ER stress-related responses and apoptosis-associated signaling in muscle cells. SELENOS siRNA knockdown in C2C12 cells/myotubes, ER stress marker measurement (GRP78, PERK, CHOP), apoptosis markers (Bax, Bcl-2, Caspase-9), differentiation assay The Journal of nutrition Medium 42025965

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Regulation of the selenoprotein SelS by glucose deprivation and endoplasmic reticulum stress - SelS is a novel glucose-regulated protein. FEBS letters 130 15063746
2007 SEPS1 protects RAW264.7 cells from pharmacological ER stress agent-induced apoptosis. Biochemical and biophysical research communications 68 17210132
2010 A combination of functional polymorphisms in the CASP8, MMP1, IL10 and SEPS1 genes affects risk of non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 65 20471133
2009 Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency. The Journal of biological chemistry 57 19398551
2014 A polymorphism in the promoter region of the selenoprotein S gene (SEPS1) contributes to Hashimoto's thyroiditis susceptibility. The Journal of clinical endocrinology and metabolism 53 24471570
2008 Genetic association of preeclampsia to the inflammatory response gene SEPS1. American journal of obstetrics and gynecology 53 18068137
2004 Relationship between serum amyloid A level and Tanis/SelS mRNA expression in skeletal muscle and adipose tissue from healthy and type 2 diabetic subjects. Diabetes 50 15161744
2011 Expression of the selenoprotein S (SELS) gene in subcutaneous adipose tissue and SELS genotype are associated with metabolic risk factors. Metabolism: clinical and experimental 49 20619427
2009 Selenoprotein S (SEPS1) gene -105G>A promoter polymorphism influences the susceptibility to gastric cancer in the Japanese population. BMC gastroenterology 46 19144102
2010 Influence of SelS gene silence on beta-Mercaptoethanol-mediated endoplasmic reticulum stress and cell apoptosis in HepG2 cells. Biochimica et biophysica acta 45 20114070
2007 Secretion of the glucose-regulated selenoprotein SEPS1 from hepatoma cells. Biochemical and biophysical research communications 38 17374524
2014 Role of selenoprotein S (SEPS1) -105G>A polymorphisms and PI3K/Akt signaling pathway in Kashin-Beck disease. Osteoarthritis and cartilage 37 25433273
2008 Role of SelS in lipopolysaccharide-induced inflammatory response in hepatoma HepG2 cells. Archives of biochemistry and biophysics 34 18675776
2008 SEPS1 gene is activated during astrocyte ischemia and shows prominent antiapoptotic effects. Journal of molecular neuroscience : MN 33 18498015
2008 Association of SelS mRNA expression in omental adipose tissue with Homa-IR and serum amyloid A in patients with type 2 diabetes mellitus. Chinese medical journal 26 18710632
2020 Cul5-type Ubiquitin Ligase KLHDC1 Contributes to the Elimination of Truncated SELENOS Produced by Failed UGA/Sec Decoding. iScience 19 32200094
2019 Interaction of Genetic Variations in NFE2L2 and SELENOS Modulates the Risk of Hashimoto's Thyroiditis. Thyroid : official journal of the American Thyroid Association 18 31426718
2007 No association of the -105 promoter polymorphism of the selenoprotein S encoding gene SEPS1 with cerebrovascular disease. European journal of neurology 18 17880573
2014 Protective effects of the SEPS1 gene on lipopolysaccharide-induced sepsis. Molecular medicine reports 15 24573439
2013 The SEPS1 G-105A polymorphism is associated with risk of spontaneous preterm birth in a Chinese population. PloS one 15 23776519
2016 Expression of human selenoprotein genes selh, selk, selm, sels, selv, and gpx-6 in various tumor cell lines. Doklady. Biochemistry and biophysics 14 27417721
2018 Association of genetic polymorphisms of SelS with Type 2 diabetes in a Chinese population. Bioscience reports 12 30413610
2023 Regorafenib activates oxidative stress by inhibiting SELENOS and potentiates oxaliplatin-induced cell death in colon cancer cells. European journal of pharmacology 11 37598924
2022 HSF1-SELENOS pathway mediated dietary inorganic Se-induced lipogenesis via the up-regulation of PPARγ expression in yellow catfish. Biochimica et biophysica acta. Gene regulatory mechanisms 10 35248747
2018 Differential regulation of cellular stress responses by the endoplasmic reticulum-resident Selenoprotein S (Seps1) in proliferating myoblasts versus myotubes. Physiological reports 10 30557449
2020 The SELS rs34713741 Polymorphism Is Associated with Susceptibility to Colorectal Cancer and Gastric Cancer: A Meta-Analysis. Genetic testing and molecular biomarkers 9 33290140
2015 Association studies of SEPS1 gene polymorphisms with Hashimoto's thyroiditis in Han Chinese. Journal of human genetics 9 26016409
2019 Correlation between SEPS1 gene polymorphism and type 2 diabetes mellitus: A preliminary study. Journal of clinical laboratory analysis 8 31265177
2019 Effect of single nucleotide polymorphisms in SEPS1 and SEPP1 on expression in the protein level in metabolic syndrome in subjects with cardiovascular disease. Molecular biology reports 6 31542866
2020 Nomogram developed with selenoprotein S (SelS) genetic variation and clinical characteristics predicting risk of coronary artery disease in a Chinese population. Cardiovascular diagnosis and therapy 5 32968632
2015 Single nucleotide polymorphism in the SEPS1 gene may contribute to the risk of various human diseases: a meta-analysis. Annals of human biology 5 26382012
2026 SELENOS Is Associated with Endoplasmic Reticulum Stress Activation in Selenium Deficiency-Induced Nutritional Muscular Dystrophy in Chicks Exposed to Heat Stress. The Journal of nutrition 0 42025965
2025 The Combined Effect Between SEPS1 Genetic Polymorphisms and Exposure to Metals on the Risk of Gestational Diabetes Mellitus. Biological trace element research 0 40163211

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