{"gene":"SEC61B","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1994,"finding":"SEC61B (Sec61-beta) is a subunit of the mammalian Sec61p complex, the core protein translocation channel of the endoplasmic reticulum. Its gamma subunit (Sec61-gamma) is homologous to yeast SSS1p and can functionally replace it in yeast, establishing evolutionary conservation of the translocon complex across eukaryotes and bacteria.","method":"Sequence determination, functional complementation in yeast, structural homology analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — functional complementation across species with sequence validation; foundational paper replicated across the field","pmids":["8107851"],"is_preprint":false},{"year":1996,"finding":"The Sec61 complex (including SEC61B as a subunit) mediates retrotranslocation of MHC class I molecules from the ER lumen to the cytosol for proteasomal degradation, a process hijacked by the HCMV US2 protein, demonstrating that the translocon can operate in reverse for ERAD.","method":"Biochemical fractionation, immunoprecipitation, proteasome inhibition, cell biology","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical demonstration of retrotranslocation via the Sec61 complex; highly cited foundational study","pmids":["8945469"],"is_preprint":false},{"year":2000,"finding":"Mammalian SEC61B is part of a ribosome-free Sec61 complex that associates with mammalian SEC62 and SEC63, forming a higher-order complex at the ER membrane analogous to the yeast post-translational translocation machinery.","method":"Biochemical fractionation, co-immunoprecipitation, sequence analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP and fractionation identifying a novel mammalian SEC61-SEC62-SEC63 complex","pmids":["10799540"],"is_preprint":false},{"year":2015,"finding":"SEC61B mRNA is a tail-anchored protein whose transcript is partially localized to the ER surface in mammalian cells via both translation-dependent and translation-independent mechanisms, independent of p180/RRBP1 and TRC40/BAT3 pathway components, suggesting that Sec61β is synthesized directly on the ER to facilitate membrane insertion.","method":"Fluorescence in situ hybridization (FISH), live-cell imaging, siRNA knockdown, cell fractionation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in single lab demonstrating ER-localized mRNA targeting","pmids":["26272916"],"is_preprint":false},{"year":2017,"finding":"Loss-of-function of SEC61B in cell line models results in defective maturation and trafficking of polycystin-1, placing SEC61B in the ER protein biogenesis pathway as a regulator of polycystin-1 processing. SEC61B loss-of-function has distinct effects on polycystin-1 biogenesis compared to loss of other PCLD genes (PRKCSH, SEC63, ALG8, GANAB).","method":"Gene inactivation in cell lines, polycystin-1 maturation/trafficking assays, whole exome sequencing","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — cell line KO with defined molecular phenotype; replicated in two papers from same group (PMIDs 28375157 and 28862642)","pmids":["28375157","28862642"],"is_preprint":false},{"year":2017,"finding":"Endogenous SEC61B protein has reduced abundance in certain peripheral ER tubules compared to the ER sheet network, as revealed by dual-color endogenous tagging with split fluorescent proteins (GFP11/sfCherry211), demonstrating non-uniform distribution within ER subdomains.","method":"CRISPR endogenous tagging with split fluorescent proteins, super-resolution and confocal live-cell imaging","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct endogenous protein localization by split-FP tagging with functional subcellular context","pmids":["28851864"],"is_preprint":false},{"year":2017,"finding":"SEC61B was identified as part of the SEC63 interactome by affinity proteomics, confirming that SEC61B is a component of the SEC63-containing translocon complex at the ER membrane in cholangiocytes.","method":"Affinity proteomics (immunoprecipitation-MS) in HEK293T cells and H69 cholangiocytes","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — MS-based interactome with known complex members as positive controls","pmids":["28973524"],"is_preprint":false},{"year":2019,"finding":"DDR1 nuclear translocation requires its interaction with SEC61B (a component of the Sec61 translocon), as well as nonmuscle myosin IIA and β-actin. This interaction enables collagen-activated DDR1 to move from the ER/membrane to the nucleus where it drives collagen IV transcription.","method":"Co-immunoprecipitation, biochemical fractionation, immunofluorescence, mutant DDR1 constructs","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and imaging showing SEC61B-DDR1 interaction required for nuclear translocation with functional transcriptional readout","pmids":["31383731"],"is_preprint":false},{"year":2021,"finding":"SEC61B anchored to the ER lumen (as SEC61b-TurboID) selectively labels proteins that transit through the classical secretory pathway via proximity biotinylation, validating that SEC61B resides in the ER translocon and that transiting secretory proteins pass through its proximity.","method":"Proximity labeling (TurboID), in vivo mouse model, quantitative proteomics","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo proximity labeling with functional validation in whole-animal system, orthogonally confirmed by secretome proteomics","pmids":["34471136"],"is_preprint":false},{"year":2021,"finding":"SEC61B expression is decreased in dendritic cells following LPS-induced reticulophagy (FAM134B-mediated), consistent with SEC61B being selectively degraded during ER-phagy of ER membrane subdomains.","method":"Western blotting, FAM134B siRNA knockdown, LPS stimulation time course","journal":"Zhonghua shao shang yu chuang mian xiu fu za zhi","confidence":"Low","confidence_rationale":"Tier 3 — single lab, Western blot only, indirect readout of ER-phagy","pmids":["37805802"],"is_preprint":false},{"year":2021,"finding":"Let-7b-5p upregulates SERP1 (stress-associated ER protein 1), which modulates its chaperone protein SEC61B during ER stress response, activating the unfolded protein response via PERK-CHOP pathway.","method":"miRNA mimic/inhibitor transfection, qPCR, Western blot, in vitro and in vivo PE models","journal":"IUBMB life","confidence":"Low","confidence_rationale":"Tier 3 — indirect modulation of SEC61B; single lab, no direct SEC61B mechanistic assay","pmids":["32534478"],"is_preprint":false},{"year":2025,"finding":"SEC61B overexpression in HEK293 cells increases calcium flux from the ER into the cytosol and decreases protein synthesis. In hyperglycemic mice and humans with diabetes, platelet SEC61B is elevated, ER stress induces SEC61B expression, and increased SEC61B causes elevated cytosolic calcium leading to platelet hyperreactivity. Pharmacological inhibition of Sec61 with anisomycin decreased platelet calcium flux and inhibited platelet aggregation in vitro and in vivo.","method":"HEK293 overexpression calcium flux assays, proteomic profiling of human/mouse platelets, pharmacological inhibition (anisomycin), in vivo thrombosis models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (overexpression, KO context, pharmacological inhibition, in vivo), replicated across human and mouse models","pmids":["40829182"],"is_preprint":false},{"year":2025,"finding":"SEC61B is required for proteolytic cleavage (by furin and furin-related enzyme SKI-1) and normal N-glycosylation of Marburg virus glycoprotein (MARV-GP) but not Ebola virus GP, revealing a virus-specific role of SEC61B in MARV-GP processing. SEC61B KO impaired SKI-1-mediated cleavage of MARV-GP and abrogated robust MARV cell entry. Blockade of the Sec61 translocon with apratoxin S4 markedly inhibited both EBOV and MARV infection.","method":"SEC61B CRISPR knockout cells, pseudovirus entry assays, Western blot for GP cleavage and glycosylation, in silico cleavage motif identification","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — KO cells with specific molecular phenotype (cleavage, glycosylation, entry) using multiple readouts; preprint, single lab","pmids":["bio_10.1101_2025.06.26.660697"],"is_preprint":true}],"current_model":"SEC61B (Sec61β) is the beta subunit of the heterotrimeric Sec61 translocon complex in the ER membrane, where it participates in co-translational protein import, ERAD retrotranslocation, and post-translational insertion of tail-anchored proteins; its mRNA is itself targeted to the ER surface for local translation, it associates with SEC62/SEC63 in a ribosome-free complex, it regulates polycystin-1 maturation (with SEC61B loss causing PCLD), it functions as an ER calcium leak channel whose ER-stress-induced upregulation drives platelet hyperreactivity in diabetes, it interacts with DDR1 to enable nuclear translocation and pro-fibrotic signaling, and it is required for furin/SKI-1-mediated proteolytic processing and N-glycosylation of Marburg virus glycoprotein."},"narrative":{"teleology":[],"mechanism_profile":null,"mechanistic_narrative":"Parse failed — see logs"},"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 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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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insertion of this tail-anchored protein on the ER. This localization is independent of p180 (RRBP1), TRC40 (ASNA1), and BAG6/BAT3.\",\n      \"method\": \"Live-cell imaging, ER fractionation, mRNA localization assays, genetic knockdown of candidate mRNA receptor and TRC pathway components\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26272916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of SEC61B function results in defective maturation and trafficking of polycystin-1 (PC1), the central determinant of cyst pathogenesis in polycystic liver disease. SEC61B inactivation in cell line models showed distinct effects on PC1 biogenesis compared to other PCLD gene products, placing SEC61B in the ER protein biogenesis pathway upstream of PC1 processing.\",\n      \"method\": \"CRISPR/Cas9 or siRNA-mediated gene inactivation in cell line models, Western blot and trafficking assays for polycystin-1 maturation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype (PC1 biogenesis defect), replicated in two separate publications (PMID 28375157 and 28862642)\",\n      \"pmids\": [\"28375157\", \"28862642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SEC61B is a component of the SEC63 complex in the ER translocon; affinity proteomics in HEK293T cells and H69 cholangiocytes identified SEC61A1 and SEC61B as interactors of SEC63, confirming their co-complex membership.\",\n      \"method\": \"Affinity proteomics (pulldown/Co-IP) in HEK293T cells and H69 cholangiocytes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reciprocal pulldown confirming known complex membership, single lab\",\n      \"pmids\": [\"28973524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Endoplasmic reticulum translocon complex SEC61B shows reduced abundance in certain peripheral ER tubules, as revealed by dual-color endogenous protein tagging with split fluorescent proteins (sfCherry2-11 and GFP11) enabling super-resolution imaging.\",\n      \"method\": \"Endogenous split fluorescent protein tagging, super-resolution microscopy (single-molecule localization)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by endogenous tagging with super-resolution imaging; single lab\",\n      \"pmids\": [\"28851864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SEC61B is required for nuclear translocation of the receptor tyrosine kinase DDR1. Upon collagen-mediated DDR1 activation, DDR1 interacts with SEC61B (a component of the Sec61 translocon) and nonmuscle myosin IIA and β-actin to translocate to the nucleus, where it binds chromatin and increases collagen IV transcription.\",\n      \"method\": \"Biochemical assays (Co-IP/pulldown), immunofluorescence, co-localization, nuclear fractionation, chromatin immunoprecipitation\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP identifying interaction, localization with functional consequence (collagen IV transcription), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31383731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC61B, anchored in the ER lumen as a tail-anchored protein, was used as an ER-anchoring scaffold for TurboID proximity labeling (iSLET), validating that SEC61B resides within the ER lumen/membrane and that proteins transiting through the classical secretory pathway pass through the Sec61 translocon.\",\n      \"method\": \"Proximity labeling (TurboID fused to Sec61b), in vivo mouse model, mass spectrometry proteomics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional validation of ER-luminal localization in vivo via proximity labeling; single lab\",\n      \"pmids\": [\"34471136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Let-7b-5p upregulates SERP1 expression, which then modulates its chaperone protein SEC61B during ER stress response, linking miRNA regulation to ER translocon function in the context of acute pulmonary embolism.\",\n      \"method\": \"miRNA mimic/inhibitor transfection, Western blot, in vitro and in vivo PE models\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method, indirect evidence for SEC61B as SERP1-modulated chaperone\",\n      \"pmids\": [\"32534478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC61B overexpression in HEK293 cells increases calcium flux from the ER into the cytosol and decreases protein synthesis, functioning as an ER calcium leak channel. In hyperglycemic mice and humans with diabetes, elevated platelet SEC61B expression caused by ER stress leads to increased cytosolic calcium and platelet hyperreactivity. Pharmacological 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, calcium flux assays, proteomic analysis of platelets, anisomycin pharmacological inhibition, in vitro and in vivo aggregation assays in hyperglycemic mouse models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution via overexpression with calcium flux assays, pharmacological inhibition in vitro and in vivo, validated in both human and mouse models\",\n      \"pmids\": [\"40829182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC61B is required for proteolytic cleavage (by furin and furin-related enzyme SKI-1) and normal N-glycosylation of Marburg virus glycoprotein (MARV-GP), but not Ebola virus GP. In SEC61B-KO cells, MARV-GP cleavage by SKI-1 and furin was impaired, and cell entry by MARV was significantly reduced. Mutation of an N-glycosylation sequon (N563D) in MARV-GP also abrogated cleavage, linking Sec61β-dependent glycosylation to protease accessibility.\",\n      \"method\": \"SEC61B knockout cells (CRISPR), furin/SKI-1 cleavage assays, N-glycosylation mutagenesis, viral pseudoparticle cell entry assays, apratoxin S4 pharmacological blockade\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — KO with defined mechanistic phenotype, mutagenesis and pharmacological validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.26.660697\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SEC61B is the beta subunit of the Sec61 translocon complex, resident in the ER membrane where its mRNA is locally translated; it facilitates ER import, glycosylation, and proteolytic maturation of client proteins (including polycystin-1 and viral glycoproteins), acts as an ER calcium leak channel whose upregulation under ER stress elevates cytosolic calcium to drive platelet hyperreactivity, and participates in non-canonical functions including DDR1 nuclear translocation and interaction with ER-phagy machinery.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"SEC61B (Sec61-beta) is a subunit of the mammalian Sec61p complex, the core protein translocation channel of the endoplasmic reticulum. Its gamma subunit (Sec61-gamma) is homologous to yeast SSS1p and can functionally replace it in yeast, establishing evolutionary conservation of the translocon complex across eukaryotes and bacteria.\",\n      \"method\": \"Sequence determination, functional complementation in yeast, structural homology analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional complementation across species with sequence validation; foundational paper replicated across the field\",\n      \"pmids\": [\"8107851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The Sec61 complex (including SEC61B as a subunit) mediates retrotranslocation of MHC class I molecules from the ER lumen to the cytosol for proteasomal degradation, a process hijacked by the HCMV US2 protein, demonstrating that the translocon can operate in reverse for ERAD.\",\n      \"method\": \"Biochemical fractionation, immunoprecipitation, proteasome inhibition, cell biology\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical demonstration of retrotranslocation via the Sec61 complex; highly cited foundational study\",\n      \"pmids\": [\"8945469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mammalian SEC61B is part of a ribosome-free Sec61 complex that associates with mammalian SEC62 and SEC63, forming a higher-order complex at the ER membrane analogous to the yeast post-translational translocation machinery.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and fractionation identifying a novel mammalian SEC61-SEC62-SEC63 complex\",\n      \"pmids\": [\"10799540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SEC61B mRNA is a tail-anchored protein whose transcript is partially localized to the ER surface in mammalian cells via both translation-dependent and translation-independent mechanisms, independent of p180/RRBP1 and TRC40/BAT3 pathway components, suggesting that Sec61β is synthesized directly on the ER to facilitate membrane insertion.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH), live-cell imaging, siRNA knockdown, cell fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in single lab demonstrating ER-localized mRNA targeting\",\n      \"pmids\": [\"26272916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss-of-function of SEC61B in cell line models results in defective maturation and trafficking of polycystin-1, placing SEC61B in the ER protein biogenesis pathway as a regulator of polycystin-1 processing. SEC61B loss-of-function has distinct effects on polycystin-1 biogenesis compared to loss of other PCLD genes (PRKCSH, SEC63, ALG8, GANAB).\",\n      \"method\": \"Gene inactivation in cell lines, polycystin-1 maturation/trafficking assays, whole exome sequencing\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell line KO with defined molecular phenotype; replicated in two papers from same group (PMIDs 28375157 and 28862642)\",\n      \"pmids\": [\"28375157\", \"28862642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Endogenous SEC61B protein has reduced abundance in certain peripheral ER tubules compared to the ER sheet network, as revealed by dual-color endogenous tagging with split fluorescent proteins (GFP11/sfCherry211), demonstrating non-uniform distribution within ER subdomains.\",\n      \"method\": \"CRISPR endogenous tagging with split fluorescent proteins, super-resolution and confocal live-cell imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct endogenous protein localization by split-FP tagging with functional subcellular context\",\n      \"pmids\": [\"28851864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SEC61B was identified as part of the SEC63 interactome by affinity proteomics, confirming that SEC61B is a component of the SEC63-containing translocon complex at the ER membrane in cholangiocytes.\",\n      \"method\": \"Affinity proteomics (immunoprecipitation-MS) in HEK293T cells and H69 cholangiocytes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-based interactome with known complex members as positive controls\",\n      \"pmids\": [\"28973524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DDR1 nuclear translocation requires its interaction with SEC61B (a component of the Sec61 translocon), as well as nonmuscle myosin IIA and β-actin. This interaction enables collagen-activated DDR1 to move from the ER/membrane to the nucleus where it drives collagen IV transcription.\",\n      \"method\": \"Co-immunoprecipitation, biochemical fractionation, immunofluorescence, mutant DDR1 constructs\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and imaging showing SEC61B-DDR1 interaction required for nuclear translocation with functional transcriptional readout\",\n      \"pmids\": [\"31383731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC61B anchored to the ER lumen (as SEC61b-TurboID) selectively labels proteins that transit through the classical secretory pathway via proximity biotinylation, validating that SEC61B resides in the ER translocon and that transiting secretory proteins pass through its proximity.\",\n      \"method\": \"Proximity labeling (TurboID), in vivo mouse model, quantitative proteomics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo proximity labeling with functional validation in whole-animal system, orthogonally confirmed by secretome proteomics\",\n      \"pmids\": [\"34471136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC61B expression is decreased in dendritic cells following LPS-induced reticulophagy (FAM134B-mediated), consistent with SEC61B being selectively degraded during ER-phagy of ER membrane subdomains.\",\n      \"method\": \"Western blotting, FAM134B siRNA knockdown, LPS stimulation time course\",\n      \"journal\": \"Zhonghua shao shang yu chuang mian xiu fu za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Western blot only, indirect readout of ER-phagy\",\n      \"pmids\": [\"37805802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Let-7b-5p upregulates SERP1 (stress-associated ER protein 1), which modulates its chaperone protein SEC61B during ER stress response, activating the unfolded protein response via PERK-CHOP pathway.\",\n      \"method\": \"miRNA mimic/inhibitor transfection, qPCR, Western blot, in vitro and in vivo PE models\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — indirect modulation of SEC61B; single lab, no direct SEC61B mechanistic assay\",\n      \"pmids\": [\"32534478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC61B overexpression in HEK293 cells increases calcium flux from the ER into the cytosol and decreases protein synthesis. In hyperglycemic mice and humans with diabetes, platelet SEC61B is elevated, ER stress induces SEC61B expression, and increased SEC61B causes elevated cytosolic calcium leading to platelet hyperreactivity. Pharmacological inhibition of Sec61 with anisomycin decreased platelet calcium flux and inhibited platelet aggregation in vitro and in vivo.\",\n      \"method\": \"HEK293 overexpression calcium flux assays, proteomic profiling of human/mouse platelets, pharmacological inhibition (anisomycin), in vivo thrombosis models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (overexpression, KO context, pharmacological inhibition, in vivo), replicated across human and mouse models\",\n      \"pmids\": [\"40829182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC61B is required for proteolytic cleavage (by furin and furin-related enzyme SKI-1) and normal N-glycosylation of Marburg virus glycoprotein (MARV-GP) but not Ebola virus GP, revealing a virus-specific role of SEC61B in MARV-GP processing. SEC61B KO impaired SKI-1-mediated cleavage of MARV-GP and abrogated robust MARV cell entry. Blockade of the Sec61 translocon with apratoxin S4 markedly inhibited both EBOV and MARV infection.\",\n      \"method\": \"SEC61B CRISPR knockout cells, pseudovirus entry assays, Western blot for GP cleavage and glycosylation, in silico cleavage motif identification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO cells with specific molecular phenotype (cleavage, glycosylation, entry) using multiple readouts; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.06.26.660697\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SEC61B (Sec61β) is the beta subunit of the heterotrimeric Sec61 translocon complex in the ER membrane, where it participates in co-translational protein import, ERAD retrotranslocation, and post-translational insertion of tail-anchored proteins; its mRNA is itself targeted to the ER surface for local translation, it associates with SEC62/SEC63 in a ribosome-free complex, it regulates polycystin-1 maturation (with SEC61B loss causing PCLD), it functions as an ER calcium leak channel whose ER-stress-induced upregulation drives platelet hyperreactivity in diabetes, it interacts with DDR1 to enable nuclear translocation and pro-fibrotic signaling, and it is required for furin/SKI-1-mediated proteolytic processing and N-glycosylation of Marburg virus glycoprotein.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n"}