{"gene":"SELENOS","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2004,"finding":"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.","method":"Cell treatment with ER stress inducers, Western blot for protein levels, overexpression with viability assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, multiple orthogonal methods (gene expression, protein quantification, overexpression rescue), but no mutagenesis or reconstitution","pmids":["15063746"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Overexpression studies, siRNA knockdown, cell viability/apoptosis assays with pharmacological ER stress agents","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain- and loss-of-function in the same system, two orthogonal perturbations, single lab","pmids":["17210132"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Brefeldin A and cycloheximide inhibitor studies, sandwich ELISA, serum fractionation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibition of secretion pathway plus direct serum detection, single lab, multiple methods","pmids":["17374524"],"is_preprint":false},{"year":2008,"finding":"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.","method":"siRNA knockdown, ROS measurement, NO/iNOS assay, RT-PCR, ELISA for SAA1, GPx activity assay","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with multiple biochemical readouts, single lab","pmids":["18675776"],"is_preprint":false},{"year":2008,"finding":"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.","method":"RNA differential display, siRNA knockdown, OGD cell injury assay","journal":"Journal of molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with defined phenotypic readout and stress induction, single lab","pmids":["18498015"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Transfection/overexpression, GRP78 promoter-reporter assay, ATF6 Western blot, NF-κB activity assay, glutathione peroxidase activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple reporter and biochemical assays in single lab with clear mechanistic readouts","pmids":["19398551"],"is_preprint":false},{"year":2010,"finding":"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.","method":"siRNA knockdown, sodium selenite supplementation, apoptosis assay, Western blot for GRP78","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain- and loss-of-function with apoptosis readout, single lab","pmids":["20114070"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vivo siRNA knockdown in LPS-sepsis mouse model, Western blot for p38 MAPK phosphorylation, ELISA for cytokines, biochemical organ damage markers","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vivo loss-of-function with multiple biochemical readouts, single lab","pmids":["24573439"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Nrf2 knockout mouse model, siRNA knockdown in thyroid cell line, immunohistochemistry, Nrf2 activity assay","journal":"Thyroid","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic KO and siRNA in two model systems, cross-validated with human tissue IHC, single lab","pmids":["31426718"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-IP/ubiquitin ligase identification, KLHDC1 knockdown in U2OS cells, proteasome inhibition, ROS measurement, cell death assay","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional validation with both KLHDC1 and SELENOS knockdown, multiple orthogonal readouts (proteasomal degradation, ROS, cell death), mechanistically rigorous single study","pmids":["32200094"],"is_preprint":false},{"year":2018,"finding":"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.","method":"siRNA knockdown (two constructs), cell viability assay, H2O2 measurement, GSH:GSSG ratio, RT-PCR for stress markers","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two siRNA constructs with multiple biochemical readouts in two cell types, single lab","pmids":["30557449"],"is_preprint":false},{"year":2023,"finding":"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.","method":"SELENOS knockdown, ROS measurement, Western blot for signaling pathway activation, mouse xenograft model","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function validated in vivo in xenograft model plus in vitro mechanistic readouts, single lab","pmids":["37598924"],"is_preprint":false},{"year":2022,"finding":"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.","method":"RNA interference (SELENOS and PPARγ), ChIP for HSF1 binding, Western blot, lipid/triglyceride measurement, enzyme activity assays","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNAi epistasis with ChIP validation of upstream transcription factor, multiple biochemical readouts; ortholog (fish model) with pathway conserved with mammals","pmids":["35248747"],"is_preprint":false},{"year":2026,"finding":"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.","method":"SELENOS siRNA knockdown in C2C12 cells/myotubes, ER stress marker measurement (GRP78, PERK, CHOP), apoptosis markers (Bax, Bcl-2, Caspase-9), differentiation assay","journal":"The Journal of nutrition","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with multiple molecular readouts in two cell states, single study","pmids":["42025965"],"is_preprint":false}],"current_model":"SELENOS (SelS/SEPS1) is an ER-resident transmembrane selenoprotein that functions as an antioxidant and component of the ERAD retro-translocation machinery: it suppresses ROS production via oxidoreductase activity (with its inactive truncated form degraded by the Cul5 ubiquitin ligase KLHDC1), reduces ER stress by dampening the unfolded protein response (ATF6, GRP78, NF-κB), protects cells from ER stress-induced apoptosis, regulates inflammatory cytokine production (TNF-α, IL-6, ROS, NO, SAA1) partly through the p38 MAPK pathway, and participates in a bidirectional positive feedback loop with the Nrf2 antioxidant transcription factor; in metabolic contexts it can also activate the IRE1α-XBP1s-PPARγ lipogenic axis downstream of HSF1-driven transcription."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2004,"claim":"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","pmids":["15063746"],"confidence":"Medium","gaps":["No molecular activity defined","Mechanism of redox protection not resolved"]},{"year":2007,"claim":"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","pmids":["17210132","17374524"],"confidence":"Medium","gaps":["Function of the secreted form unknown","Pro-survival molecular mechanism not defined"]},{"year":2008,"claim":"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","pmids":["18675776","18498015"],"confidence":"Medium","gaps":["Direct enzymatic activity not demonstrated","Causal chain from SELENOS loss to inflammatory output indirect"]},{"year":2009,"claim":"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","pmids":["19398551"],"confidence":"Medium","gaps":["Whether effects are direct or downstream not resolved","No structural basis for chaperone-like action"]},{"year":2010,"claim":"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","pmids":["20114070"],"confidence":"Medium","gaps":["Apoptotic effectors directly engaged not identified"]},{"year":2014,"claim":"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","pmids":["24573439"],"confidence":"Medium","gaps":["Direct link between SELENOS and p38 activation not established","Cell type responsible in vivo unclear"]},{"year":2018,"claim":"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","pmids":["30557449"],"confidence":"Medium","gaps":["Basis for myoblast vs myotube difference unexplained"]},{"year":2019,"claim":"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","pmids":["31426718"],"confidence":"Medium","gaps":["Molecular mechanism of reciprocal regulation not defined","Direct vs indirect feedback unresolved"]},{"year":2020,"claim":"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","pmids":["32200094"],"confidence":"High","gaps":["Substrate/partner of the oxidoreductase activity not identified","Structural basis of KLHDC1 recognition not resolved"]},{"year":2022,"claim":"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","pmids":["35248747"],"confidence":"Medium","gaps":["Conservation of axis in mammals not directly tested","Mechanism linking SELENOS to IRE1α activation unclear"]},{"year":2023,"claim":"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","pmids":["37598924"],"confidence":"Medium","gaps":["Direct enzymatic contribution to ROS levels not isolated"]},{"year":2026,"claim":"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","pmids":["42025965"],"confidence":"Medium","gaps":["Apoptotic effector directly regulated not pinned down"]},{"year":null,"claim":"The direct molecular substrate of SELENOS oxidoreductase activity and its precise role within the ERAD retro-translocation machinery remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,7]}],"complexes":[],"partners":["KLHDC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BQE4","full_name":"Selenoprotein S","aliases":["VCP-interacting membrane protein"],"length_aa":189,"mass_kda":21.2,"function":"Involved in the degradation process of misfolded endoplasmic reticulum (ER) luminal proteins. Participates in the transfer of misfolded proteins from the ER to the cytosol, where they are destroyed by the proteasome in a ubiquitin-dependent manner. Probably acts by serving as a linker between DERL1, which mediates the retrotranslocation of misfolded proteins into the cytosol, and the ATPase complex VCP, which mediates the translocation and ubiquitination","subcellular_location":"Endoplasmic reticulum membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9BQE4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SELENOS","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"VCP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SELENOS","total_profiled":1310},"omim":[{"mim_id":"607918","title":"SELENOPROTEIN S; SELENOS","url":"https://www.omim.org/entry/607918"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SELENOS"},"hgnc":{"alias_symbol":["SELS","MGC2553","SBBI8","AD-015","SEPS1"],"prev_symbol":["VIMP"]},"alphafold":{"accession":"Q9BQE4","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BQE4","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SELENOS","jax_strain_url":"https://www.jax.org/strain/search?query=SELENOS"},"sequence":{"accession":"Q9BQE4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BQE4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BQE4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BQE4"}},"corpus_meta":[{"pmid":"15063746","id":"PMC_15063746","title":"Regulation of the selenoprotein SelS by glucose deprivation and endoplasmic reticulum stress - SelS is a novel glucose-regulated protein.","date":"2004","source":"FEBS 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19398551","citation_count":57,"is_preprint":false},{"pmid":"24471570","id":"PMC_24471570","title":"A polymorphism in the promoter region of the selenoprotein S gene (SEPS1) contributes to Hashimoto's thyroiditis susceptibility.","date":"2014","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24471570","citation_count":53,"is_preprint":false},{"pmid":"18068137","id":"PMC_18068137","title":"Genetic association of preeclampsia to the inflammatory response gene SEPS1.","date":"2008","source":"American journal of obstetrics and gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/18068137","citation_count":53,"is_preprint":false},{"pmid":"15161744","id":"PMC_15161744","title":"Relationship between serum amyloid A level and Tanis/SelS mRNA expression in skeletal muscle and adipose tissue from healthy and type 2 diabetic subjects.","date":"2004","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/15161744","citation_count":50,"is_preprint":false},{"pmid":"20619427","id":"PMC_20619427","title":"Expression of the selenoprotein S (SELS) gene in subcutaneous adipose tissue and SELS genotype are associated with metabolic risk factors.","date":"2011","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/20619427","citation_count":49,"is_preprint":false},{"pmid":"19144102","id":"PMC_19144102","title":"Selenoprotein S (SEPS1) gene -105G>A promoter polymorphism influences the susceptibility to gastric cancer in the Japanese population.","date":"2009","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/19144102","citation_count":46,"is_preprint":false},{"pmid":"20114070","id":"PMC_20114070","title":"Influence of SelS gene silence on beta-Mercaptoethanol-mediated endoplasmic reticulum stress and cell apoptosis in HepG2 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Biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/27417721","citation_count":14,"is_preprint":false},{"pmid":"30413610","id":"PMC_30413610","title":"Association of genetic polymorphisms of SelS with Type 2 diabetes in a Chinese population.","date":"2018","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/30413610","citation_count":12,"is_preprint":false},{"pmid":"37598924","id":"PMC_37598924","title":"Regorafenib activates oxidative stress by inhibiting SELENOS and potentiates oxaliplatin-induced cell death in colon cancer cells.","date":"2023","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37598924","citation_count":11,"is_preprint":false},{"pmid":"35248747","id":"PMC_35248747","title":"HSF1-SELENOS pathway mediated dietary inorganic Se-induced lipogenesis via the up-regulation of PPARγ expression in yellow catfish.","date":"2022","source":"Biochimica et biophysica acta. 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Overexpression of SelS increased Min6 cell resistance to oxidative stress-induced toxicity, indicating a role in regulating cellular redox balance.\",\n      \"method\": \"Cell treatment with ER stress inducers, Western blot for protein levels, overexpression with viability assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, multiple orthogonal methods (gene expression, protein quantification, overexpression rescue), but no mutagenesis or reconstitution\",\n      \"pmids\": [\"15063746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression studies, siRNA knockdown, cell viability/apoptosis assays with pharmacological ER stress agents\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain- and loss-of-function in the same system, two orthogonal perturbations, single lab\",\n      \"pmids\": [\"17210132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Brefeldin A and cycloheximide inhibitor studies, sandwich ELISA, serum fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibition of secretion pathway plus direct serum detection, single lab, multiple methods\",\n      \"pmids\": [\"17374524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, ROS measurement, NO/iNOS assay, RT-PCR, ELISA for SAA1, GPx activity assay\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with multiple biochemical readouts, single lab\",\n      \"pmids\": [\"18675776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"RNA differential display, siRNA knockdown, OGD cell injury assay\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with defined phenotypic readout and stress induction, single lab\",\n      \"pmids\": [\"18498015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Transfection/overexpression, GRP78 promoter-reporter assay, ATF6 Western blot, NF-κB activity assay, glutathione peroxidase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple reporter and biochemical assays in single lab with clear mechanistic readouts\",\n      \"pmids\": [\"19398551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, sodium selenite supplementation, apoptosis assay, Western blot for GRP78\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain- and loss-of-function with apoptosis readout, single lab\",\n      \"pmids\": [\"20114070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo siRNA knockdown in LPS-sepsis mouse model, Western blot for p38 MAPK phosphorylation, ELISA for cytokines, biochemical organ damage markers\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo loss-of-function with multiple biochemical readouts, single lab\",\n      \"pmids\": [\"24573439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Nrf2 knockout mouse model, siRNA knockdown in thyroid cell line, immunohistochemistry, Nrf2 activity assay\",\n      \"journal\": \"Thyroid\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic KO and siRNA in two model systems, cross-validated with human tissue IHC, single lab\",\n      \"pmids\": [\"31426718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP/ubiquitin ligase identification, KLHDC1 knockdown in U2OS cells, proteasome inhibition, ROS measurement, cell death assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional validation with both KLHDC1 and SELENOS knockdown, multiple orthogonal readouts (proteasomal degradation, ROS, cell death), mechanistically rigorous single study\",\n      \"pmids\": [\"32200094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown (two constructs), cell viability assay, H2O2 measurement, GSH:GSSG ratio, RT-PCR for stress markers\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two siRNA constructs with multiple biochemical readouts in two cell types, single lab\",\n      \"pmids\": [\"30557449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"SELENOS knockdown, ROS measurement, Western blot for signaling pathway activation, mouse xenograft model\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function validated in vivo in xenograft model plus in vitro mechanistic readouts, single lab\",\n      \"pmids\": [\"37598924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"RNA interference (SELENOS and PPARγ), ChIP for HSF1 binding, Western blot, lipid/triglyceride measurement, enzyme activity assays\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNAi epistasis with ChIP validation of upstream transcription factor, multiple biochemical readouts; ortholog (fish model) with pathway conserved with mammals\",\n      \"pmids\": [\"35248747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"SELENOS siRNA knockdown in C2C12 cells/myotubes, ER stress marker measurement (GRP78, PERK, CHOP), apoptosis markers (Bax, Bcl-2, Caspase-9), differentiation assay\",\n      \"journal\": \"The Journal of nutrition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with multiple molecular readouts in two cell states, single study\",\n      \"pmids\": [\"42025965\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SELENOS (SelS/SEPS1) is an ER-resident transmembrane selenoprotein that functions as an antioxidant and component of the ERAD retro-translocation machinery: it suppresses ROS production via oxidoreductase activity (with its inactive truncated form degraded by the Cul5 ubiquitin ligase KLHDC1), reduces ER stress by dampening the unfolded protein response (ATF6, GRP78, NF-κB), protects cells from ER stress-induced apoptosis, regulates inflammatory cytokine production (TNF-α, IL-6, ROS, NO, SAA1) partly through the p38 MAPK pathway, and participates in a bidirectional positive feedback loop with the Nrf2 antioxidant transcription factor; in metabolic contexts it can also activate the IRE1α-XBP1s-PPARγ lipogenic axis downstream of HSF1-driven transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SELENOS (SelS/SEPS1) is an endoplasmic reticulum-associated selenoprotein that links ER homeostasis to cellular redox balance, inflammation, and stress-induced apoptosis [#0, #5]. Its expression is induced by glucose deprivation and pharmacological ER stress in parallel with GRP78, marking it as a glucose-regulated, stress-responsive protein [#0]. In the face of ER stress, SELENOS acts protectively: it lowers active ATF6, suppresses GRP78 promoter activity and NF-\\u03baB signaling to dampen the unfolded protein and ER overload responses [#5], and its loss sensitizes macrophages, astrocytes, and muscle cells to ER stress-induced death [#1, #4, #13]. 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 [#9]. Through this antioxidant and ER-protective role it restrains inflammatory mediator production\\u2014ROS, NO, iNOS, SAA1, TNF-\\u03b1 and IL-6\\u2014partly by inhibiting p38 MAPK signaling [#3, #7]. SELENOS participates in a bidirectional positive feedback loop with the Nrf2 antioxidant program [#8], and in metabolic settings is transcriptionally driven by HSF1 to activate an XBP1s/PPAR\\u03b3 lipogenic axis [#12]. A secreted form of SELENOS is detectable in serum and associates with LDL/VLDL fractions [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"ER stress inducer treatment, Western blot, and overexpression viability assay in HepG2 and Min6 cells\",\n      \"pmids\": [\"15063746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular activity defined\", \"Mechanism of redox protection not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Overexpression and siRNA in RAW264.7 macrophages; Brefeldin A/cycloheximide secretion blockade, ELISA, and serum fractionation in hepatoma cells\",\n      \"pmids\": [\"17210132\", \"17374524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the secreted form unknown\", \"Pro-survival molecular mechanism not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown with ROS/NO/iNOS/SAA1/GPx readouts in HepG2; differential display and siRNA in an OGD astrocyte injury model\",\n      \"pmids\": [\"18675776\", \"18498015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic activity not demonstrated\", \"Causal chain from SELENOS loss to inflammatory output indirect\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided mechanistic detail on ER stress suppression by showing SELENOS lowers active ATF6, GRP78 promoter activity, and NF-\\u03baB signaling, defining a chaperone-like dampening of the UPR/ER overload response.\",\n      \"evidence\": \"Overexpression with reporter assays, ATF6 Western blot, and NF-\\u03baB activity assay in a ZAAT-induced ER stress model in HepG2\",\n      \"pmids\": [\"19398551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether effects are direct or downstream not resolved\", \"No structural basis for chaperone-like action\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown and selenite supplementation with apoptosis and GRP78 readouts in HepG2\",\n      \"pmids\": [\"20114070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apoptotic effectors directly engaged not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified p38 MAPK as a signaling route through which SELENOS suppresses inflammatory cytokines in vivo, connecting its loss to systemic organ damage in sepsis.\",\n      \"evidence\": \"In vivo siRNA knockdown in an LPS-sepsis mouse model with p38 phosphorylation Western blot, cytokine ELISA, and organ damage markers\",\n      \"pmids\": [\"24573439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between SELENOS and p38 activation not established\", \"Cell type responsible in vivo unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a cell-type-specific antioxidant function in muscle, where SELENOS knockdown elevates oxidative and ER stress in myoblasts but not differentiated myotubes.\",\n      \"evidence\": \"Two-construct siRNA knockdown with H2O2, GSH:GSSG, viability, and stress marker readouts in C2C12 myoblasts and myotubes\",\n      \"pmids\": [\"30557449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for myoblast vs myotube difference unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed SELENOS in a bidirectional positive feedback loop with the Nrf2 antioxidant transcription factor, with relevance to autoimmune thyroid disease.\",\n      \"evidence\": \"Nrf2 knockout mice, siRNA in PCCL3 thyroid cells, and Hashimoto's thyroiditis tissue IHC\",\n      \"pmids\": [\"31426718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of reciprocal regulation not defined\", \"Direct vs indirect feedback unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP ligase identification, KLHDC1 and SELENOS knockdown, proteasome inhibition, ROS and cell-death assays in U2OS cells\",\n      \"pmids\": [\"32200094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate/partner of the oxidoreductase activity not identified\", \"Structural basis of KLHDC1 recognition not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected SELENOS to lipid metabolism by establishing an HSF1-SELENOS-IRE1\\u03b1-XBP1s-PPAR\\u03b3 lipogenic axis responsive to selenium form.\",\n      \"evidence\": \"RNAi epistasis (SELENOS, PPAR\\u03b3), ChIP for HSF1 promoter binding, and lipid measurements in yellow catfish liver\",\n      \"pmids\": [\"35248747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of axis in mammals not directly tested\", \"Mechanism linking SELENOS to IRE1\\u03b1 activation unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Validated SELENOS as an antioxidant ROS suppressor in cancer, where its loss sensitizes colorectal cells to drug-induced, ROS-mediated killing in vivo.\",\n      \"evidence\": \"SELENOS knockdown with ROS, JNK/p38/ER stress signaling Western blot, and mouse xenograft in colorectal cancer cells\",\n      \"pmids\": [\"37598924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic contribution to ROS levels not isolated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown with ER stress and apoptosis marker panels and differentiation assays in C2C12 cells and myotubes\",\n      \"pmids\": [\"42025965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apoptotic effector directly regulated not pinned down\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular substrate of SELENOS oxidoreductase activity and its precise role within the ERAD retro-translocation machinery remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified redox substrate\", \"No structural model of SELENOS in the ERAD channel\", \"Reconciliation of ROS-promoting (oxidoreductase) and ROS-suppressing (antioxidant) roles unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KLHDC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}