{"gene":"SEC61B","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":2017,"finding":"SEC61B loss-of-function results in defective maturation and trafficking of polycystin-1 (PC1), the central determinant of cyst pathogenesis in polycystic liver disease. Cell line knockout of SEC61B demonstrated distinct effects on PC1 biogenesis compared to other PCLD gene knockouts, placing SEC61B in the ER protein biogenesis pathway upstream of PC1 maturation.","method":"CRISPR/siRNA-based gene inactivation in cell line models with functional readout of polycystin-1 maturation and trafficking","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated independently in two separate publications (PMIDs 28375157 and 28862642) from the same cohort study, loss-of-function with defined molecular phenotype (PC1 maturation defect)","pmids":["28375157","28862642"],"is_preprint":false},{"year":2015,"finding":"Sec61b mRNA is partially localized to the surface of the ER in mammalian cells via both translation-dependent and translation-independent mechanisms, facilitating co-translational insertion of the Sec61β tail-anchored protein directly into the ER membrane. This localization was found to be independent of p180 (RRBP1) and TRC pathway components TRC40 and BAT3.","method":"Fluorescence microscopy (live imaging and FISH), subcellular fractionation, and dominant-negative/knockdown experiments for TRC40, BAT3, and p180","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (ER membrane insertion), single lab with multiple orthogonal methods","pmids":["26272916"],"is_preprint":false},{"year":2017,"finding":"Super-resolution imaging of endogenously tagged SEC61B (using split sfCherry2) revealed that SEC61B has reduced abundance in certain peripheral ER tubules compared to the ER sheet network, establishing a non-uniform subcellular distribution within the ER.","method":"Dual-color endogenous protein tagging with split fluorescent proteins (sfCherry211 and GFP11) and super-resolution microscopy","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct subcellular localization by live imaging of endogenously tagged protein, single lab, single method","pmids":["28851864"],"is_preprint":false},{"year":2019,"finding":"SEC61B, as a component of the Sec61 translocon, was identified as a binding partner of SEC63 by affinity proteomics (PLD interactome mapping), confirming its physical association with SEC63 within the ER translocon complex in cholangiocytes.","method":"Affinity proteomics (AP-MS) in HEK293T cells and H69 cholangiocytes","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — affinity pulldown with MS identification, confirmed in two cell types","pmids":["28973524"],"is_preprint":false},{"year":2019,"finding":"DDR1 nuclear translocation requires interaction with SEC61B (a component of the Sec61 translocon), nonmuscle myosin IIA, and β-actin. Collagen-activated DDR1 uses SEC61B as part of the nuclear translocation machinery to regulate collagen IV transcription.","method":"Biochemical assays and immunofluorescence with co-immunoprecipitation of DDR1 with SEC61B; loss-of-function experiments","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/pulldown identifying SEC61B as binding partner of DDR1, with functional consequence (nuclear translocation), single lab","pmids":["31383731"],"is_preprint":false},{"year":2021,"finding":"Sec61b-TurboID fusion (ER lumen-anchored) efficiently labels proteins transiting through the classical secretory pathway in vivo, demonstrating that SEC61B resides in the ER lumen-facing portion of the translocon and can serve as an anchor for proximity labeling of ER-transiting secretory proteins.","method":"In vivo proximity labeling (TurboID) anchored via Sec61b in mouse liver, validated by proteomics of labeled plasma proteins","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vivo localization with proteomic validation, single lab, multiple orthogonal methods","pmids":["34471136"],"is_preprint":false},{"year":2025,"finding":"SEC61B overexpression in HEK293 cells increased calcium flux from the ER into the cytosol and decreased protein synthesis, consistent with SEC61B acting as an ER calcium leak channel. In hyperglycemic mice and diabetic humans, elevated platelet SEC61B was associated with increased cytosolic calcium and platelet hyperreactivity. ER stress induced SEC61B expression, and inhibition of Sec61 with anisomycin decreased platelet calcium flux and inhibited platelet aggregation in vitro and in vivo.","method":"SEC61B overexpression in HEK293 cells with calcium flux measurement; hyperglycemic mouse models; pharmacological inhibition of Sec61 (anisomycin) in vitro and in vivo; proteomic profiling of human and mouse platelets","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (OE in cells, animal models, pharmacological inhibition, human samples), all converging on SEC61B as ER calcium leak channel regulating platelet calcium homeostasis","pmids":["40829182"],"is_preprint":false},{"year":2025,"finding":"SEC61B (Sec61β subunit) is required for proteolytic cleavage and normal N-glycosylation of Marburg virus (MARV) glycoprotein, but is dispensable for MARV-GP expression itself. In SEC61B-KO cells, SKI-1-mediated cleavage of MARV-GP was impaired. Loss of SEC61B modestly inhibited both EBOV and MARV infection, while pharmacological Sec61 blockade with apratoxin S4 more markedly inhibited infection.","method":"SEC61B knockout cells (CRISPR), glycoprotein cleavage assays, N-glycosylation analysis, viral entry assays, pharmacological inhibition with apratoxin S4, in silico identification of SKI-1 cleavage motif","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with defined molecular phenotype (GP cleavage, glycosylation), multiple orthogonal methods (KO, mutagenesis, pharmacology), single preprint lab","pmids":["bio_10.1101_2025.06.26.660697"],"is_preprint":true},{"year":2020,"finding":"SERP1 (stress-associated ER protein 1) activation modulates its chaperone protein SEC61B during ER stress responses, placing SEC61B downstream of SERP1 in the ER stress pathway in lung epithelial cells.","method":"miRNA mimic/inhibitor transfection with Western blotting for SERP1 and SEC61B; in vitro and in vivo acute pulmonary embolism models","journal":"IUBMB life","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect mechanistic placement (SERP1 modulates SEC61B), limited mechanistic detail in abstract","pmids":["32534478"],"is_preprint":false},{"year":2026,"finding":"SEC61B is recruited to stress granules along with calnexin (CANX) under ER stress conditions; inhibition of SG formation by Micranthin B prevented this SEC61B/CANX recruitment, reduced accumulation of misfolded proteins, and alleviated ER stress in hepatocytes.","method":"Drug treatment (Micranthin B) in HFHC diet mouse model and PA-stimulated hepatocytes; Western blotting and immunofluorescence for SEC61B and SG markers","journal":"Chinese journal of natural medicines","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect observation of SEC61B recruitment to stress granules as part of drug mechanism study, no direct manipulation of SEC61B","pmids":["42215158"],"is_preprint":false}],"current_model":"SEC61B is the beta subunit of the Sec61 translocon complex in the ER membrane, where it facilitates co-translational protein import (its mRNA is targeted to the ER surface for direct insertion), supports maturation and trafficking of client proteins such as polycystin-1 (with loss-of-function causing cystogenesis), participates in nuclear translocation of activated DDR1 as a binding partner, functions as an ER calcium leak channel whose upregulation (e.g., by ER stress in diabetes) increases cytosolic calcium and platelet hyperreactivity, and is required for proteolytic processing and N-glycosylation of Marburg virus glycoprotein during viral entry."},"narrative":{"mechanistic_narrative":"Parse failed — see logs","teleology":[],"mechanism_profile":null},"prefetch_data":{"uniprot":{"accession":"P60468","full_name":"Protein transport protein Sec61 subunit beta","aliases":[],"length_aa":96,"mass_kda":10.0,"function":"Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER) (PubMed:12475939). Forms a ribosome receptor and a gated pore in the ER membrane, both functions required for cotranslational translocation of nascent polypeptides (PubMed:12475939). The SEC61 channel is also involved in ER membrane insertion of transmembrane proteins: it mediates membrane insertion of the first few transmembrane segments of proteins, while insertion of subsequent transmembrane regions of multi-pass membrane proteins is mediated by the multi-pass translocon (MPT) complex (PubMed:32820719, PubMed:36261522). The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER (PubMed:19121997)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P60468/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC61B","classification":"Common Essential","n_dependent_lines":660,"n_total_lines":1208,"dependency_fraction":0.5463576158940397},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000106803","cell_line_id":"CID000456","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"ERN1","stoichiometry":10.0},{"gene":"PGRMC2","stoichiometry":10.0},{"gene":"PGRMC1","stoichiometry":10.0},{"gene":"RPL34","stoichiometry":10.0},{"gene":"POR","stoichiometry":10.0},{"gene":"SSR3","stoichiometry":10.0},{"gene":"SEC61A1","stoichiometry":10.0},{"gene":"GNL3","stoichiometry":10.0},{"gene":"SEC62","stoichiometry":10.0},{"gene":"CCDC47","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000456","total_profiled":1310},"omim":[{"mim_id":"617674","title":"STRESS-ASSOCIATED ENDOPLASMIC RETICULUM PROTEIN 1; SERP1","url":"https://www.omim.org/entry/617674"},{"mim_id":"614371","title":"DENGUE VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/614371"},{"mim_id":"612374","title":"STIMULATOR OF INTERFERON RESPONSE cGAMP INTERACTOR 1; STING1","url":"https://www.omim.org/entry/612374"},{"mim_id":"610305","title":"DER1-LIKE DOMAIN FAMILY, MEMBER 3; DERL3","url":"https://www.omim.org/entry/610305"},{"mim_id":"610304","title":"DER1-LIKE DOMAIN FAMILY, MEMBER 2; DERL2","url":"https://www.omim.org/entry/610304"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC61B"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P60468","domains":[{"cath_id":"1.20.5","chopping":"68-96","consensus_level":"medium","plddt":76.7797,"start":68,"end":96}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P60468","model_url":"https://alphafold.ebi.ac.uk/files/AF-P60468-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P60468-F1-predicted_aligned_error_v6.png","plddt_mean":57.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC61B","jax_strain_url":"https://www.jax.org/strain/search?query=SEC61B"},"sequence":{"accession":"P60468","fasta_url":"https://rest.uniprot.org/uniprotkb/P60468.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P60468/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P60468"}},"corpus_meta":[{"pmid":"29038287","id":"PMC_29038287","title":"Genetic Complexity of Autosomal Dominant 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Cell line knockout of SEC61B demonstrated distinct effects on PC1 biogenesis compared to other PCLD gene knockouts, placing SEC61B in the ER protein biogenesis pathway upstream of PC1 maturation.\",\n      \"method\": \"CRISPR/siRNA-based gene inactivation in cell line models with functional readout of polycystin-1 maturation and trafficking\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated independently in two separate publications (PMIDs 28375157 and 28862642) from the same cohort study, loss-of-function with defined molecular phenotype (PC1 maturation defect)\",\n      \"pmids\": [\"28375157\", \"28862642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sec61b mRNA is partially localized to the surface of the ER in mammalian cells via both translation-dependent and translation-independent mechanisms, facilitating co-translational insertion of the Sec61β tail-anchored protein directly into the ER membrane. This localization was found to be independent of p180 (RRBP1) and TRC pathway components TRC40 and BAT3.\",\n      \"method\": \"Fluorescence microscopy (live imaging and FISH), subcellular fractionation, and dominant-negative/knockdown experiments for TRC40, BAT3, and p180\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (ER membrane insertion), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26272916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Super-resolution imaging of endogenously tagged SEC61B (using split sfCherry2) revealed that SEC61B has reduced abundance in certain peripheral ER tubules compared to the ER sheet network, establishing a non-uniform subcellular distribution within the ER.\",\n      \"method\": \"Dual-color endogenous protein tagging with split fluorescent proteins (sfCherry211 and GFP11) and super-resolution microscopy\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct subcellular localization by live imaging of endogenously tagged protein, single lab, single method\",\n      \"pmids\": [\"28851864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SEC61B, as a component of the Sec61 translocon, was identified as a binding partner of SEC63 by affinity proteomics (PLD interactome mapping), confirming its physical association with SEC63 within the ER translocon complex in cholangiocytes.\",\n      \"method\": \"Affinity proteomics (AP-MS) in HEK293T cells and H69 cholangiocytes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — affinity pulldown with MS identification, confirmed in two cell types\",\n      \"pmids\": [\"28973524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DDR1 nuclear translocation requires interaction with SEC61B (a component of the Sec61 translocon), nonmuscle myosin IIA, and β-actin. Collagen-activated DDR1 uses SEC61B as part of the nuclear translocation machinery to regulate collagen IV transcription.\",\n      \"method\": \"Biochemical assays and immunofluorescence with co-immunoprecipitation of DDR1 with SEC61B; loss-of-function experiments\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/pulldown identifying SEC61B as binding partner of DDR1, with functional consequence (nuclear translocation), single lab\",\n      \"pmids\": [\"31383731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sec61b-TurboID fusion (ER lumen-anchored) efficiently labels proteins transiting through the classical secretory pathway in vivo, demonstrating that SEC61B resides in the ER lumen-facing portion of the translocon and can serve as an anchor for proximity labeling of ER-transiting secretory proteins.\",\n      \"method\": \"In vivo proximity labeling (TurboID) anchored via Sec61b in mouse liver, validated by proteomics of labeled plasma proteins\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vivo localization with proteomic validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34471136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC61B overexpression in HEK293 cells increased calcium flux from the ER into the cytosol and decreased protein synthesis, consistent with SEC61B acting as an ER calcium leak channel. In hyperglycemic mice and diabetic humans, elevated platelet SEC61B was associated with increased cytosolic calcium and platelet hyperreactivity. ER stress induced SEC61B expression, and inhibition of Sec61 with anisomycin decreased platelet calcium flux and inhibited platelet aggregation in vitro and in vivo.\",\n      \"method\": \"SEC61B overexpression in HEK293 cells with calcium flux measurement; hyperglycemic mouse models; pharmacological inhibition of Sec61 (anisomycin) in vitro and in vivo; proteomic profiling of human and mouse platelets\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (OE in cells, animal models, pharmacological inhibition, human samples), all converging on SEC61B as ER calcium leak channel regulating platelet calcium homeostasis\",\n      \"pmids\": [\"40829182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC61B (Sec61β subunit) is required for proteolytic cleavage and normal N-glycosylation of Marburg virus (MARV) glycoprotein, but is dispensable for MARV-GP expression itself. In SEC61B-KO cells, SKI-1-mediated cleavage of MARV-GP was impaired. Loss of SEC61B modestly inhibited both EBOV and MARV infection, while pharmacological Sec61 blockade with apratoxin S4 more markedly inhibited infection.\",\n      \"method\": \"SEC61B knockout cells (CRISPR), glycoprotein cleavage assays, N-glycosylation analysis, viral entry assays, pharmacological inhibition with apratoxin S4, in silico identification of SKI-1 cleavage motif\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with defined molecular phenotype (GP cleavage, glycosylation), multiple orthogonal methods (KO, mutagenesis, pharmacology), single preprint lab\",\n      \"pmids\": [\"bio_10.1101_2025.06.26.660697\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SERP1 (stress-associated ER protein 1) activation modulates its chaperone protein SEC61B during ER stress responses, placing SEC61B downstream of SERP1 in the ER stress pathway in lung epithelial cells.\",\n      \"method\": \"miRNA mimic/inhibitor transfection with Western blotting for SERP1 and SEC61B; in vitro and in vivo acute pulmonary embolism models\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect mechanistic placement (SERP1 modulates SEC61B), limited mechanistic detail in abstract\",\n      \"pmids\": [\"32534478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC61B is recruited to stress granules along with calnexin (CANX) under ER stress conditions; inhibition of SG formation by Micranthin B prevented this SEC61B/CANX recruitment, reduced accumulation of misfolded proteins, and alleviated ER stress in hepatocytes.\",\n      \"method\": \"Drug treatment (Micranthin B) in HFHC diet mouse model and PA-stimulated hepatocytes; Western blotting and immunofluorescence for SEC61B and SG markers\",\n      \"journal\": \"Chinese journal of natural medicines\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect observation of SEC61B recruitment to stress granules as part of drug mechanism study, no direct manipulation of SEC61B\",\n      \"pmids\": [\"42215158\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC61B is the beta subunit of the Sec61 translocon complex in the ER membrane, where it facilitates co-translational protein import (its mRNA is targeted to the ER surface for direct insertion), supports maturation and trafficking of client proteins such as polycystin-1 (with loss-of-function causing cystogenesis), participates in nuclear translocation of activated DDR1 as a binding partner, functions as an ER calcium leak channel whose upregulation (e.g., by ER stress in diabetes) increases cytosolic calcium and platelet hyperreactivity, and is required for proteolytic processing and N-glycosylation of Marburg virus glycoprotein during viral entry.\"\n}\n```","stage2_raw":"","audit_flag":{"gene":"SEC61B","tier":"BEHAVIOR","verdict":"Model-behavior concern","subtype":"model_safety_refusal","uniprot_band":"medium","rules_fired":"R10","issue":"R10: API stop_reason='refusal' at stage2"},"evaluation":null}