{"gene":"TMEM109","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2016,"finding":"Snd3 (TMEM109 ortholog) functions as part of the SND (SRP-independent targeting) pathway in yeast, working together with Snd1 and Snd2 to target proteins to the ER in parallel with the SRP and GET pathways. Genetic epistasis showed that the SND proteins can synthetically compensate for loss of both SRP and GET pathways, acting as a backup ER targeting system.","method":"Systematic visual screen in S. cerevisiae, genetic epistasis (synthetic lethality/compensation with SRP and GET pathway mutants), loss-of-function targeting assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple orthogonal targeting assays, replicated across yeast and mammalian contexts, foundational paper widely cited","pmids":["27905431"],"is_preprint":false},{"year":2022,"finding":"TMEM109 was characterized as hSnd3, the human ortholog of yeast Snd3 and a component of the human SND ER-targeting pathway. Depletion of hSnd2 from HeLa cells combined with proteomic analysis identified TMEM109/hSnd3 as a novel component of the SND pathway. SND pathway clients are predominantly membrane proteins with N-terminal, central, or C-terminal targeting signals, distinct from SRP and TRC pathway substrates.","method":"siRNA knockdown of hSnd2 in HeLa cells, quantitative proteomics, differential protein abundance analysis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus knockdown in human cells, single lab, two orthogonal methods","pmids":["36139500"],"is_preprint":false},{"year":2025,"finding":"SND3 (TMEM109 ortholog) is a membrane insertase with an atypical fold that promotes integral membrane protein (IMP) insertion via a membrane-embedded hydrophilic groove that disrupts the lipid bilayer. Cryo-EM structure of a ribosome-associated SND3 translocon complex revealed it comprises SND3, the complete SEC61 translocon, CCDC47, and TRAPα. Within this complex, the SEC61β N-terminus works together with CCDC47 to prevent substrate access to the SEC61 translocon, redirecting substrates to SND3.","method":"Cryo-electron microscopy structure determination, molecular dynamics simulations, structural and sequence comparisons","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with molecular dynamics simulations providing mechanistic detail; peer-reviewed publication","pmids":["41162385"],"is_preprint":false},{"year":2025,"finding":"SND3 (TMEM109 ortholog from Chaetomium thermophilum) is a membrane insertase of novel fold that disrupts the lipid bilayer via a membrane-embedded hydrophilic groove to promote co-translational IMP insertion. The SND3 translocon complex includes SEC61 translocon, CCDC47, and TRAPα. Structural comparisons indicate this is a distinct multipass translocon for insertion of multipass IMPs in fungi and euglenozoan parasites.","method":"Cryo-EM structure determination, molecular dynamics simulations, structural and sequence comparisons","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with MD simulations; preprint version of the published Nature Communications paper (PMID 41162385), same findings","pmids":[],"is_preprint":true},{"year":2011,"finding":"MG23 (TMEM109) has three transmembrane segments and forms homo-oligomeric, bowl-shaped assemblies with a central pore. After reconstitution into planar phospholipid bilayers, purified MG23 functions as a voltage-dependent, cation-conducting channel permeable to both K+ and Ca2+, with multiple channels gating together.","method":"Hydropathicity profiling, limited proteolysis, chemical cross-linking, single-particle 3D cryo-EM reconstruction, reconstitution into planar phospholipid bilayers, electrophysiology","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of channel activity plus structural reconstruction and biochemical characterization in one rigorous study","pmids":["21381722"],"is_preprint":false},{"year":2017,"finding":"MG23 (TMEM109) is a Zn2+-regulated Ca2+-permeable channel in the sarcoplasmic reticulum. Elevating cytosolic Zn2+ to 1 nM increased MG23 activity in SR vesicles incorporated into phospholipid bilayers. The full-open state current amplitude of MG23 is consistent with that previously attributed to RyR2 sub-conductance gating, suggesting MG23 contributes to SR Ca2+ leakage in heart failure. MG23 expression is increased in H9C2 cells under ischemic conditions coinciding with elevated intracellular Zn2+.","method":"Planar phospholipid bilayer electrophysiology with cardiac SR vesicles, voltage-clamp, H9C2 cell ischemia model, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological reconstitution in bilayers with defined ionic concentrations, supported by cell-based experiments","pmids":["28630041"],"is_preprint":false},{"year":2010,"finding":"MG23 (TMEM109) overexpression in HEK293T cells specifically enhanced apoptosis triggered by etoposide (a DNA-damaging drug). Genetic deletion of MG23 in mice reduced susceptibility of thymocytes to DNA damage-induced apoptosis after whole-body irradiation, with attenuated p53 induction in MG23-knockout thymocytes.","method":"Overexpression in HEK293T cells, MG23 knockout mouse model, whole-body irradiation, flow cytometry apoptosis assay, Western blot for p53","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vivo knockout with defined cellular phenotype and molecular marker (p53), plus gain-of-function overexpression, single lab","pmids":["20060811"],"is_preprint":false},{"year":2013,"finding":"MG23 (TMEM109) protects against UVC-induced cell death. Knockdown of MG23 enhanced UVC-induced apoptosis. The small heat shock protein αB-crystallin (αBC) was identified as a MG23 binding molecule, and expression of ER-anchored αBC lowered UVC sensitivity, suggesting MG23 acts by accumulating αBC near the ER.","method":"siRNA knockdown, co-immunoprecipitation/binding assay to identify αBC as MG23 partner, overexpression of ER-anchored αBC, UVC cell death assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP identifying binding partner plus knockdown phenotype, two orthogonal methods, single lab","pmids":["23542032"],"is_preprint":false},{"year":2026,"finding":"MG23 (TMEM109) knockout in mice protects against angiotensin II-induced pressure overload cardiac hypertrophy and dysfunction. AngII treatment increased MG23 protein expression in WT hearts. Mg23-KO cardiomyocytes displayed altered Ca2+-spark profiles consistent with reduced SR Ca2+ leak. Overexpression of MG23 in H9C2 cells reduced SR Ca2+ store levels. No alteration in expression of key Ca2+-handling proteins was found in Mg23-KO hearts.","method":"Mg23 knockout mouse model, AngII osmotic pump infusion, pressure-volume catheter measurements in vivo, Western blot, histology/immunofluorescence, live-cell Ca2+ imaging with Fluo-4, H9C2 overexpression","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with defined cardiac phenotype plus multiple readouts (Ca2+ dynamics, fibrosis, function), single lab","pmids":["41568959"],"is_preprint":false},{"year":2021,"finding":"Yeast Snd3 (TMEM109 ortholog) is an ER protein that is central to nucleus-vacuole junction (NVJ) formation. Snd3 interacts with NVJ tethers and supports their targeting to contact sites. Upon glucose exhaustion, Snd3 relocalizes from the ER to NVJs and promotes NVJ expansion regulated by central glucose signaling pathways. Glucose replenishment induces rapid dissociation of Snd3 from NVJs preceding slow NVJ disassembly.","method":"Fluorescence microscopy (live imaging and colocalization), co-immunoprecipitation, genetic deletion, glucose signaling pathway analysis in S. cerevisiae","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence, reciprocal interaction data, single lab with multiple orthogonal approaches","pmids":["33472077"],"is_preprint":false},{"year":2025,"finding":"ZBTB20 transcriptionally represses TMEM109 expression in glioblastoma cells, as demonstrated by dual-luciferase reporter assay and chromatin immunoprecipitation. TMEM109 overexpression inhibits ferroptosis while TMEM109 knockdown promotes ferroptosis in GBM cells. Co-transfection showed TMEM109 overexpression can reverse the pro-ferroptotic effect of ZBTB20.","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), gain- and loss-of-function (overexpression and knockdown), co-transfection rescue experiment","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase reporter establishing direct transcriptional repression, functional rescue by co-transfection, single lab","pmids":["40999982"],"is_preprint":false}],"current_model":"TMEM109 (also known as MG23/hSnd3/Snd3) is a multi-transmembrane ER/SR protein that functions in at least two distinct capacities: (1) as the membrane insertase component of the SND (SRP-independent targeting) pathway, forming a ribosome-associated translocon complex with SEC61, CCDC47, and TRAPα to co-translationally insert multipass integral membrane proteins into the ER membrane via a hydrophilic groove that disrupts the lipid bilayer; and (2) as a voltage-dependent, non-selective cation channel (permeable to Ca2+ and K+) on ER/SR and nuclear membranes that is activated by Zn2+ and contributes to SR Ca2+ leak under pathophysiological conditions, with additional roles in modulating DNA damage-induced apoptosis through interaction with αB-crystallin and regulation of NVJ membrane contact sites in response to nutrient signaling."},"narrative":{"mechanistic_narrative":"TMEM109 is a multi-transmembrane endoplasmic/sarcoplasmic reticulum protein that operates as the membrane-insertase component of the SRP-independent (SND) protein-targeting pathway, originally defined in yeast where Snd3, together with Snd1 and Snd2, provides a backup route for delivering proteins to the ER in parallel with the SRP and GET pathways [PMID:27905431, PMID:36139500]. Cryo-EM of a ribosome-associated SND3 translocon shows an insertase of atypical fold that drives co-translational integral membrane protein insertion through a membrane-embedded hydrophilic groove that locally disrupts the lipid bilayer; in this complex SND3 associates with the SEC61 translocon, CCDC47, and TRAPα, where the SEC61β N-terminus and CCDC47 occlude the SEC61 channel to redirect substrates toward SND3 [PMID:41162385]. Independently of its insertase role, reconstituted TMEM109 (MG23) forms homo-oligomeric, bowl-shaped assemblies with a central pore that conduct a voltage-dependent, non-selective cation current permeable to both K+ and Ca2+ [PMID:21381722], and this channel is activated by cytosolic Zn2+ in cardiac SR membranes, contributing to SR Ca2+ leak [PMID:28630041]. Consistent with a pathophysiological Ca2+-handling role, TMEM109 protein rises during cardiac stress and its loss in mice reduces SR Ca2+ leak and protects against angiotensin II-induced cardiac hypertrophy and dysfunction [PMID:41568959]. TMEM109 additionally modulates DNA-damage- and UV-induced apoptosis, in part through binding the small heat-shock protein αB-crystallin [PMID:20060811, PMID:23542032], and its expression is transcriptionally repressed by ZBTB20 to influence ferroptosis in glioblastoma cells [PMID:40999982].","teleology":[{"year":2016,"claim":"Established that the TMEM109 ortholog Snd3 defines a third ER-targeting route, answering how proteins reach the ER when SRP and GET pathways fail.","evidence":"Systematic visual screen and genetic epistasis in S. cerevisiae showing synthetic compensation with SRP and GET mutants","pmids":["27905431"],"confidence":"High","gaps":["Did not define the human ortholog or molecular insertase mechanism","Client repertoire and biochemical activity unresolved"]},{"year":2022,"claim":"Extended the SND pathway to humans by identifying TMEM109 as hSnd3, addressing whether the yeast backup-targeting system is conserved.","evidence":"siRNA knockdown of hSnd2 in HeLa cells with quantitative proteomics of client abundance","pmids":["36139500"],"confidence":"Medium","gaps":["Single lab","Direct insertase activity of human TMEM109 not demonstrated","Membrane topology within a translocon undefined"]},{"year":2025,"claim":"Resolved the molecular mechanism of SND-pathway insertion, showing TMEM109/SND3 is a membrane insertase that opens a hydrophilic groove within a SEC61/CCDC47/TRAPα translocon.","evidence":"Cryo-EM of a ribosome-associated SND3 translocon with molecular dynamics simulations","pmids":["41162385"],"confidence":"High","gaps":["Substrate selection rules between SEC61 and SND3 not fully defined","Human complex structure inferred from fungal ortholog"]},{"year":2011,"claim":"Demonstrated that TMEM109/MG23 is itself an ion channel, answering whether the protein has an activity independent of protein targeting.","evidence":"Cryo-EM 3D reconstruction plus reconstitution into planar phospholipid bilayers and electrophysiology of purified MG23","pmids":["21381722"],"confidence":"High","gaps":["Physiological gating stimulus not identified","Native membrane context and selectivity regulation unknown"]},{"year":2017,"claim":"Identified Zn2+ as a physiological activator of the channel and linked it to cardiac SR Ca2+ leak, connecting channel activity to disease.","evidence":"Bilayer electrophysiology of cardiac SR vesicles at defined Zn2+ concentrations plus H9C2 ischemia model","pmids":["28630041"],"confidence":"High","gaps":["Distinction from RyR2 sub-conductance gating in situ not fully resolved","In vivo contribution to heart failure not tested here"]},{"year":2026,"claim":"Tested the in vivo cardiac role, showing TMEM109 loss reduces SR Ca2+ leak and protects against pressure-overload hypertrophy.","evidence":"Mg23 knockout mice with AngII infusion, pressure-volume measurements, Fluo-4 Ca2+ imaging, and H9C2 overexpression","pmids":["41568959"],"confidence":"Medium","gaps":["Single lab","Mechanistic link between channel activity and hypertrophy signaling not fully dissected","No change in canonical Ca2+-handling proteins leaves leak mechanism partly open"]},{"year":2010,"claim":"Linked TMEM109 to DNA-damage-induced apoptosis, raising the question of how an ER channel modulates cell death.","evidence":"MG23 overexpression in HEK293T cells and knockout mice with irradiation, apoptosis assays, and p53 Western blot","pmids":["20060811"],"confidence":"Medium","gaps":["Molecular pathway connecting MG23 to p53 induction unresolved","Single lab"]},{"year":2013,"claim":"Provided a candidate effector for the apoptosis role by identifying αB-crystallin as a TMEM109 binding partner.","evidence":"siRNA knockdown, co-immunoprecipitation, and ER-anchored αBC overexpression with UVC death assays","pmids":["23542032"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","Direct binding interface and stoichiometry undefined"]},{"year":2021,"claim":"Showed that the yeast ortholog Snd3 regulates nucleus-vacuole junction contact sites in response to glucose signaling, adding a membrane-contact-site function.","evidence":"Live-cell fluorescence microscopy, co-immunoprecipitation, and genetic deletion in S. cerevisiae under glucose manipulation","pmids":["33472077"],"confidence":"Medium","gaps":["Conservation of NVJ role to human TMEM109 not shown","Relationship to insertase function unclear"]},{"year":2025,"claim":"Placed TMEM109 in a transcriptional circuit controlling glioblastoma ferroptosis, identifying ZBTB20 as a direct repressor.","evidence":"Dual-luciferase reporter, ChIP, gain/loss-of-function, and co-transfection rescue in GBM cells","pmids":["40999982"],"confidence":"Medium","gaps":["Mechanism by which TMEM109 suppresses ferroptosis undefined","Single lab"]},{"year":null,"claim":"How TMEM109's two activities — SND-pathway membrane insertase and ER/SR cation channel — are coordinated within a single protein, and whether they share structural elements, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No study reconciles the insertase fold with the channel pore","Whether the SND complex and channel oligomer are mutually exclusive states is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,7]}],"complexes":["SND3 ribosome-associated translocon (SND3-SEC61-CCDC47-TRAPα)"],"partners":["SEC61","CCDC47","TRAPΑ","CRYAB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BVC6","full_name":"Voltage-gated monoatomic cation channel TMEM109","aliases":["Mitsugumin-23","Mg23","Transmembrane protein 109"],"length_aa":243,"mass_kda":26.2,"function":"Functions as a voltage-gated monoatomic cation channel permeable to both potassium and calcium (By similarity). Plays a role in the cellular response to DNA damage (PubMed:23542032)","subcellular_location":"Nucleus outer membrane; Endoplasmic reticulum membrane; Sarcoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9BVC6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM109","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":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMEM109","total_profiled":1310},"omim":[{"mim_id":"619168","title":"TRANSMEMBRANE PROTEIN 109; TMEM109","url":"https://www.omim.org/entry/619168"},{"mim_id":"123590","title":"CRYSTALLIN, ALPHA-B; CRYAB","url":"https://www.omim.org/entry/123590"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear membrane","reliability":"Approved"},{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM109"},"hgnc":{"alias_symbol":["MGC5508","SND3","hSND3","Mg23"],"prev_symbol":[]},"alphafold":{"accession":"Q9BVC6","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVC6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVC6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVC6-F1-predicted_aligned_error_v6.png","plddt_mean":67.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM109","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM109"},"sequence":{"accession":"Q9BVC6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BVC6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BVC6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVC6"}},"corpus_meta":[{"pmid":"27905431","id":"PMC_27905431","title":"The SND proteins constitute an alternative targeting route to the endoplasmic reticulum.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27905431","citation_count":170,"is_preprint":false},{"pmid":"17971101","id":"PMC_17971101","title":"Review of studies of androgen treatment of female-to-male transsexuals: effects and risks of administration of androgens to females.","date":"2007","source":"The journal of sexual medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17971101","citation_count":79,"is_preprint":false},{"pmid":"26228553","id":"PMC_26228553","title":"New and notable ion-channels in the sarcoplasmic/endoplasmic reticulum: do they support the process of intracellular Ca²⁺ release?","date":"2014","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26228553","citation_count":60,"is_preprint":false},{"pmid":"3158213","id":"PMC_3158213","title":"Examination of irreversible platelet-fibrinogen interactions.","date":"1985","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/3158213","citation_count":51,"is_preprint":false},{"pmid":"37816143","id":"PMC_37816143","title":"Banana MaNAC1 activates secondary cell wall cellulose biosynthesis to enhance chilling resistance in fruit.","date":"2023","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/37816143","citation_count":34,"is_preprint":false},{"pmid":"33472077","id":"PMC_33472077","title":"Snd3 controls nucleus-vacuole junctions in response to glucose signaling.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33472077","citation_count":28,"is_preprint":false},{"pmid":"28630041","id":"PMC_28630041","title":"Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28630041","citation_count":24,"is_preprint":false},{"pmid":"10219597","id":"PMC_10219597","title":"Isolation of a specific DNA fragment and development of a PCR-based method for the detection of Mycobacterium genavense.","date":"1999","source":"FEMS immunology and medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10219597","citation_count":23,"is_preprint":false},{"pmid":"21381722","id":"PMC_21381722","title":"Mitsugumin 23 forms a massive bowl-shaped assembly and cation-conducting channel.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21381722","citation_count":19,"is_preprint":false},{"pmid":"36139500","id":"PMC_36139500","title":"Proteomics Identifies Substrates and a Novel Component in hSnd2-Dependent ER Protein Targeting.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36139500","citation_count":16,"is_preprint":false},{"pmid":"23542032","id":"PMC_23542032","title":"Protective role of the endoplasmic reticulum protein mitsugumin23 against ultraviolet C-induced cell death.","date":"2013","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23542032","citation_count":16,"is_preprint":false},{"pmid":"20060811","id":"PMC_20060811","title":"Facilitation of DNA damage-induced apoptosis by endoplasmic reticulum protein mitsugumin23.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20060811","citation_count":11,"is_preprint":false},{"pmid":"16706028","id":"PMC_16706028","title":"[Study on sini decoction in treatment of intestinal ischemia-reperfusion injury in rats: mechanism relating to oxygen radical and bcl-2 protein].","date":"2006","source":"Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/16706028","citation_count":3,"is_preprint":false},{"pmid":"40999982","id":"PMC_40999982","title":"ZBTB20 promotes ferroptosis through inhibiting TMEM109 expression in glioblastoma cells.","date":"2025","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40999982","citation_count":1,"is_preprint":false},{"pmid":"41617037","id":"PMC_41617037","title":"Bone marrow proteomic profiling reveals TMEM109 as a biomarker for relapse in thrombotic thrombocytopenic purpura.","date":"2026","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/41617037","citation_count":1,"is_preprint":false},{"pmid":"41162385","id":"PMC_41162385","title":"SND3 is the membrane insertase within a distinct SEC61 translocon complex.","date":"2025","source":"Nature 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translocon","date":"2025-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.08.663624","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11406,"output_tokens":3144,"usd":0.040689,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10682,"output_tokens":3327,"usd":0.068293,"stage2_stop_reason":"end_turn"},"total_usd":0.108982,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Snd3 (TMEM109 ortholog) functions as part of the SND (SRP-independent targeting) pathway in yeast, working together with Snd1 and Snd2 to target proteins to the ER in parallel with the SRP and GET pathways. Genetic epistasis showed that the SND proteins can synthetically compensate for loss of both SRP and GET pathways, acting as a backup ER targeting system.\",\n      \"method\": \"Systematic visual screen in S. cerevisiae, genetic epistasis (synthetic lethality/compensation with SRP and GET pathway mutants), loss-of-function targeting assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple orthogonal targeting assays, replicated across yeast and mammalian contexts, foundational paper widely cited\",\n      \"pmids\": [\"27905431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM109 was characterized as hSnd3, the human ortholog of yeast Snd3 and a component of the human SND ER-targeting pathway. Depletion of hSnd2 from HeLa cells combined with proteomic analysis identified TMEM109/hSnd3 as a novel component of the SND pathway. SND pathway clients are predominantly membrane proteins with N-terminal, central, or C-terminal targeting signals, distinct from SRP and TRC pathway substrates.\",\n      \"method\": \"siRNA knockdown of hSnd2 in HeLa cells, quantitative proteomics, differential protein abundance analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus knockdown in human cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"36139500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SND3 (TMEM109 ortholog) is a membrane insertase with an atypical fold that promotes integral membrane protein (IMP) insertion via a membrane-embedded hydrophilic groove that disrupts the lipid bilayer. Cryo-EM structure of a ribosome-associated SND3 translocon complex revealed it comprises SND3, the complete SEC61 translocon, CCDC47, and TRAPα. Within this complex, the SEC61β N-terminus works together with CCDC47 to prevent substrate access to the SEC61 translocon, redirecting substrates to SND3.\",\n      \"method\": \"Cryo-electron microscopy structure determination, molecular dynamics simulations, structural and sequence comparisons\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with molecular dynamics simulations providing mechanistic detail; peer-reviewed publication\",\n      \"pmids\": [\"41162385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SND3 (TMEM109 ortholog from Chaetomium thermophilum) is a membrane insertase of novel fold that disrupts the lipid bilayer via a membrane-embedded hydrophilic groove to promote co-translational IMP insertion. The SND3 translocon complex includes SEC61 translocon, CCDC47, and TRAPα. Structural comparisons indicate this is a distinct multipass translocon for insertion of multipass IMPs in fungi and euglenozoan parasites.\",\n      \"method\": \"Cryo-EM structure determination, molecular dynamics simulations, structural and sequence comparisons\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with MD simulations; preprint version of the published Nature Communications paper (PMID 41162385), same findings\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MG23 (TMEM109) has three transmembrane segments and forms homo-oligomeric, bowl-shaped assemblies with a central pore. After reconstitution into planar phospholipid bilayers, purified MG23 functions as a voltage-dependent, cation-conducting channel permeable to both K+ and Ca2+, with multiple channels gating together.\",\n      \"method\": \"Hydropathicity profiling, limited proteolysis, chemical cross-linking, single-particle 3D cryo-EM reconstruction, reconstitution into planar phospholipid bilayers, electrophysiology\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of channel activity plus structural reconstruction and biochemical characterization in one rigorous study\",\n      \"pmids\": [\"21381722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MG23 (TMEM109) is a Zn2+-regulated Ca2+-permeable channel in the sarcoplasmic reticulum. Elevating cytosolic Zn2+ to 1 nM increased MG23 activity in SR vesicles incorporated into phospholipid bilayers. The full-open state current amplitude of MG23 is consistent with that previously attributed to RyR2 sub-conductance gating, suggesting MG23 contributes to SR Ca2+ leakage in heart failure. MG23 expression is increased in H9C2 cells under ischemic conditions coinciding with elevated intracellular Zn2+.\",\n      \"method\": \"Planar phospholipid bilayer electrophysiology with cardiac SR vesicles, voltage-clamp, H9C2 cell ischemia model, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological reconstitution in bilayers with defined ionic concentrations, supported by cell-based experiments\",\n      \"pmids\": [\"28630041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MG23 (TMEM109) overexpression in HEK293T cells specifically enhanced apoptosis triggered by etoposide (a DNA-damaging drug). Genetic deletion of MG23 in mice reduced susceptibility of thymocytes to DNA damage-induced apoptosis after whole-body irradiation, with attenuated p53 induction in MG23-knockout thymocytes.\",\n      \"method\": \"Overexpression in HEK293T cells, MG23 knockout mouse model, whole-body irradiation, flow cytometry apoptosis assay, Western blot for p53\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vivo knockout with defined cellular phenotype and molecular marker (p53), plus gain-of-function overexpression, single lab\",\n      \"pmids\": [\"20060811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MG23 (TMEM109) protects against UVC-induced cell death. Knockdown of MG23 enhanced UVC-induced apoptosis. The small heat shock protein αB-crystallin (αBC) was identified as a MG23 binding molecule, and expression of ER-anchored αBC lowered UVC sensitivity, suggesting MG23 acts by accumulating αBC near the ER.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation/binding assay to identify αBC as MG23 partner, overexpression of ER-anchored αBC, UVC cell death assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP identifying binding partner plus knockdown phenotype, two orthogonal methods, single lab\",\n      \"pmids\": [\"23542032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MG23 (TMEM109) knockout in mice protects against angiotensin II-induced pressure overload cardiac hypertrophy and dysfunction. AngII treatment increased MG23 protein expression in WT hearts. Mg23-KO cardiomyocytes displayed altered Ca2+-spark profiles consistent with reduced SR Ca2+ leak. Overexpression of MG23 in H9C2 cells reduced SR Ca2+ store levels. No alteration in expression of key Ca2+-handling proteins was found in Mg23-KO hearts.\",\n      \"method\": \"Mg23 knockout mouse model, AngII osmotic pump infusion, pressure-volume catheter measurements in vivo, Western blot, histology/immunofluorescence, live-cell Ca2+ imaging with Fluo-4, H9C2 overexpression\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with defined cardiac phenotype plus multiple readouts (Ca2+ dynamics, fibrosis, function), single lab\",\n      \"pmids\": [\"41568959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Snd3 (TMEM109 ortholog) is an ER protein that is central to nucleus-vacuole junction (NVJ) formation. Snd3 interacts with NVJ tethers and supports their targeting to contact sites. Upon glucose exhaustion, Snd3 relocalizes from the ER to NVJs and promotes NVJ expansion regulated by central glucose signaling pathways. Glucose replenishment induces rapid dissociation of Snd3 from NVJs preceding slow NVJ disassembly.\",\n      \"method\": \"Fluorescence microscopy (live imaging and colocalization), co-immunoprecipitation, genetic deletion, glucose signaling pathway analysis in S. cerevisiae\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence, reciprocal interaction data, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"33472077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZBTB20 transcriptionally represses TMEM109 expression in glioblastoma cells, as demonstrated by dual-luciferase reporter assay and chromatin immunoprecipitation. TMEM109 overexpression inhibits ferroptosis while TMEM109 knockdown promotes ferroptosis in GBM cells. Co-transfection showed TMEM109 overexpression can reverse the pro-ferroptotic effect of ZBTB20.\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), gain- and loss-of-function (overexpression and knockdown), co-transfection rescue experiment\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase reporter establishing direct transcriptional repression, functional rescue by co-transfection, single lab\",\n      \"pmids\": [\"40999982\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM109 (also known as MG23/hSnd3/Snd3) is a multi-transmembrane ER/SR protein that functions in at least two distinct capacities: (1) as the membrane insertase component of the SND (SRP-independent targeting) pathway, forming a ribosome-associated translocon complex with SEC61, CCDC47, and TRAPα to co-translationally insert multipass integral membrane proteins into the ER membrane via a hydrophilic groove that disrupts the lipid bilayer; and (2) as a voltage-dependent, non-selective cation channel (permeable to Ca2+ and K+) on ER/SR and nuclear membranes that is activated by Zn2+ and contributes to SR Ca2+ leak under pathophysiological conditions, with additional roles in modulating DNA damage-induced apoptosis through interaction with αB-crystallin and regulation of NVJ membrane contact sites in response to nutrient signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM109 is a multi-transmembrane endoplasmic/sarcoplasmic reticulum protein that operates as the membrane-insertase component of the SRP-independent (SND) protein-targeting pathway, originally defined in yeast where Snd3, together with Snd1 and Snd2, provides a backup route for delivering proteins to the ER in parallel with the SRP and GET pathways [#0, #1]. Cryo-EM of a ribosome-associated SND3 translocon shows an insertase of atypical fold that drives co-translational integral membrane protein insertion through a membrane-embedded hydrophilic groove that locally disrupts the lipid bilayer; in this complex SND3 associates with the SEC61 translocon, CCDC47, and TRAPα, where the SEC61β N-terminus and CCDC47 occlude the SEC61 channel to redirect substrates toward SND3 [#2]. Independently of its insertase role, reconstituted TMEM109 (MG23) forms homo-oligomeric, bowl-shaped assemblies with a central pore that conduct a voltage-dependent, non-selective cation current permeable to both K+ and Ca2+ [#4], and this channel is activated by cytosolic Zn2+ in cardiac SR membranes, contributing to SR Ca2+ leak [#5]. Consistent with a pathophysiological Ca2+-handling role, TMEM109 protein rises during cardiac stress and its loss in mice reduces SR Ca2+ leak and protects against angiotensin II-induced cardiac hypertrophy and dysfunction [#8]. TMEM109 additionally modulates DNA-damage- and UV-induced apoptosis, in part through binding the small heat-shock protein αB-crystallin [#6, #7], and its expression is transcriptionally repressed by ZBTB20 to influence ferroptosis in glioblastoma cells [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that the TMEM109 ortholog Snd3 defines a third ER-targeting route, answering how proteins reach the ER when SRP and GET pathways fail.\",\n      \"evidence\": \"Systematic visual screen and genetic epistasis in S. cerevisiae showing synthetic compensation with SRP and GET mutants\",\n      \"pmids\": [\"27905431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the human ortholog or molecular insertase mechanism\", \"Client repertoire and biochemical activity unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the SND pathway to humans by identifying TMEM109 as hSnd3, addressing whether the yeast backup-targeting system is conserved.\",\n      \"evidence\": \"siRNA knockdown of hSnd2 in HeLa cells with quantitative proteomics of client abundance\",\n      \"pmids\": [\"36139500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct insertase activity of human TMEM109 not demonstrated\", \"Membrane topology within a translocon undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the molecular mechanism of SND-pathway insertion, showing TMEM109/SND3 is a membrane insertase that opens a hydrophilic groove within a SEC61/CCDC47/TRAPα translocon.\",\n      \"evidence\": \"Cryo-EM of a ribosome-associated SND3 translocon with molecular dynamics simulations\",\n      \"pmids\": [\"41162385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate selection rules between SEC61 and SND3 not fully defined\", \"Human complex structure inferred from fungal ortholog\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that TMEM109/MG23 is itself an ion channel, answering whether the protein has an activity independent of protein targeting.\",\n      \"evidence\": \"Cryo-EM 3D reconstruction plus reconstitution into planar phospholipid bilayers and electrophysiology of purified MG23\",\n      \"pmids\": [\"21381722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological gating stimulus not identified\", \"Native membrane context and selectivity regulation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified Zn2+ as a physiological activator of the channel and linked it to cardiac SR Ca2+ leak, connecting channel activity to disease.\",\n      \"evidence\": \"Bilayer electrophysiology of cardiac SR vesicles at defined Zn2+ concentrations plus H9C2 ischemia model\",\n      \"pmids\": [\"28630041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinction from RyR2 sub-conductance gating in situ not fully resolved\", \"In vivo contribution to heart failure not tested here\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Tested the in vivo cardiac role, showing TMEM109 loss reduces SR Ca2+ leak and protects against pressure-overload hypertrophy.\",\n      \"evidence\": \"Mg23 knockout mice with AngII infusion, pressure-volume measurements, Fluo-4 Ca2+ imaging, and H9C2 overexpression\",\n      \"pmids\": [\"41568959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic link between channel activity and hypertrophy signaling not fully dissected\", \"No change in canonical Ca2+-handling proteins leaves leak mechanism partly open\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked TMEM109 to DNA-damage-induced apoptosis, raising the question of how an ER channel modulates cell death.\",\n      \"evidence\": \"MG23 overexpression in HEK293T cells and knockout mice with irradiation, apoptosis assays, and p53 Western blot\",\n      \"pmids\": [\"20060811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway connecting MG23 to p53 induction unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided a candidate effector for the apoptosis role by identifying αB-crystallin as a TMEM109 binding partner.\",\n      \"evidence\": \"siRNA knockdown, co-immunoprecipitation, and ER-anchored αBC overexpression with UVC death assays\",\n      \"pmids\": [\"23542032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Direct binding interface and stoichiometry undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that the yeast ortholog Snd3 regulates nucleus-vacuole junction contact sites in response to glucose signaling, adding a membrane-contact-site function.\",\n      \"evidence\": \"Live-cell fluorescence microscopy, co-immunoprecipitation, and genetic deletion in S. cerevisiae under glucose manipulation\",\n      \"pmids\": [\"33472077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of NVJ role to human TMEM109 not shown\", \"Relationship to insertase function unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed TMEM109 in a transcriptional circuit controlling glioblastoma ferroptosis, identifying ZBTB20 as a direct repressor.\",\n      \"evidence\": \"Dual-luciferase reporter, ChIP, gain/loss-of-function, and co-transfection rescue in GBM cells\",\n      \"pmids\": [\"40999982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TMEM109 suppresses ferroptosis undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMEM109's two activities — SND-pathway membrane insertase and ER/SR cation channel — are coordinated within a single protein, and whether they share structural elements, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No study reconciles the insertase fold with the channel pore\", \"Whether the SND complex and channel oligomer are mutually exclusive states is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\"SND3 ribosome-associated translocon (SND3-SEC61-CCDC47-TRAPα)\"],\n    \"partners\": [\"SEC61\", \"CCDC47\", \"TRAPα\", \"CRYAB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}