{"gene":"TMEM120A","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2020,"finding":"TACAN (TMEM120A) is expressed in a subset of nociceptors; heterologous expression increases mechanically evoked currents in cell lines; purification and reconstitution in synthetic lipids generates a functional ion channel; nociceptor-specific inducible knockout decreases mechanosensitivity and reduces behavioral responses to painful mechanical stimuli but not thermal or touch stimuli.","method":"Heterologous expression in cell lines, protein purification + lipid reconstitution, nociceptor-specific inducible knockout with behavioral assays and patch-clamp electrophysiology","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — reconstitution and KO with defined phenotype in single lab; ion channel activity subsequently contested by multiple independent groups","pmids":["32084332"],"is_preprint":false},{"year":2015,"finding":"TMEM120A localizes to the nuclear envelope and is required for adipocyte differentiation; knockdown of TMEM120A alters expression of adipocyte differentiation genes (Gata3, Fasn, Glut4, Pparg, Adipoq) and reduces lipid accumulation in 3T3-L1 cells.","method":"siRNA knockdown in 3T3-L1 cells, qPCR for differentiation markers, Oil Red O staining and CARS microscopy for lipid accumulation, nuclear envelope localization by subcellular fractionation/microscopy","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype and multiple orthogonal readouts (gene expression, lipid staining, CARS) in single lab","pmids":["26024229"],"is_preprint":false},{"year":2022,"finding":"Adipocyte-specific knockout of Tmem120a disrupts fat genome organisation (repositioning of genes, enhancers, and miRNA loci between nuclear periphery and interior), broadly suppresses lipid metabolism pathway gene expression, induces myogenic gene expression, and causes a lipodystrophy syndrome in mice resembling human FPLD2 with insulin resistance and metabolic defects.","method":"Adipocyte-specific knockout mice, 3D genome organisation analysis, RNA-seq, metabolic phenotyping, comparison with FPLD2 patient cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — adipocyte-specific KO with multiple orthogonal methods (genome organisation, transcriptomics, metabolic phenotyping) and validation in human patient cells","pmids":["35027552"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of human TMEM120A reveals a tightly packed dimer with N-terminal coiled-coil domain and C-terminal transmembrane domain (6 TMs forming an α-barrel); a coenzyme A (CoA) molecule is bound in a deep pocket within the TMD; structural homology to ELOVL fatty acid elongases; no clear structural features of an ion channel pore.","method":"Single-particle cryo-EM structure determination, CoA ligand identification by mass spectrometry (companion paper Niu et al.)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent cryo-EM structures from three separate labs (Xue et al., Niu et al., Rong et al.) all converge on same dimeric architecture and CoA-binding site","pmids":["34374645","34374644","34409941"],"is_preprint":false},{"year":2021,"finding":"TACAN (TMEM120A) does not exhibit mechanosensitive ion channel activity; at high protein concentrations, reconstituted TACAN produces heterogeneous conduction levels inconsistent with a bona fide channel and most consistent with lipid bilayer disruption; cryo-EM structure shows each protomer contains a CoA cofactor (confirmed by mass spectrometry) and is structurally related to fatty acid elongase ELOVL7.","method":"Cellular patch-clamp recording, membrane reconstitution electrophysiology, single-particle cryo-EM, native mass spectrometry","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple rigorous methods (patch-clamp, reconstitution, cryo-EM, MS) in a single study; negative ion channel result replicated across multiple independent labs","pmids":["34374644"],"is_preprint":false},{"year":2021,"finding":"TMEM120A expression alone is not sufficient to mediate poking- or stretch-induced currents in cells; cryo-EM structures reveal symmetrical homodimer with six membrane-spanning helices per monomer and a CoA molecule bound in a deep cavity via specific interactions with nearby residues; mutation of a central tryptophan involved in CoA binding dramatically reduces CoA binding affinity; TMEM120A adopts distinct conformations in CoA-bound vs. apo states.","method":"Patch-clamp electrophysiology (poking and stretch), single-particle cryo-EM (CoA-bound and apo states), site-directed mutagenesis of CoA-binding residue with binding affinity measurement","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus mutagenesis of binding residue plus functional electrophysiology in single rigorous study","pmids":["34409941"],"is_preprint":false},{"year":2022,"finding":"TMEM120A co-expression specifically decreases amplitudes of mechanically activated PIEZO2 currents and increases their activation threshold in heterologous cells; TMEM120A did not inhibit PIEZO1 or TREK1; TMEM120A alone did not generate mechanically activated currents above background; siRNA knockdown of Tmem120a in mouse DRG neurons increased rapidly adapting mechanically activated current amplitudes and decreased their activation thresholds; Tmem120a and Piezo2 expression overlap in DRG neurons.","method":"Heterologous co-expression with patch-clamp electrophysiology, siRNA knockdown in primary DRG neurons with patch-clamp, in situ expression analysis","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function electrophysiology in both heterologous cells and primary neurons with specificity controls (PIEZO1, TREK1 not affected)","pmids":["35819364"],"is_preprint":false},{"year":2022,"finding":"TMEM120A overexpression inhibits Zika virus (ZIKV) replication; TMEM120A interacts with STING and promotes STING translocation from the ER to ERGIC; this enhances phosphorylation of downstream TBK1 and IRF3, resulting in expression of antiviral cytokines and interferon-stimulated genes; antiviral activity is STING-dependent.","method":"Genome-wide overexpression screen, Co-immunoprecipitation, subcellular fractionation/localization assay, TMEM120A knockdown and Tmem120a knockout (MEFs), phospho-western blot for TBK1/IRF3, cytokine/ISG expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP for interaction, localization assay for STING trafficking, KO confirmation in MEFs, pathway readouts (TBK1/IRF3 phosphorylation, ISGs), multiple orthogonal methods in single study","pmids":["35013224"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of human TACAN shows each protomer has a transmembrane globular domain (6 helices) and intracellular domain (2 helices); molecular dynamics simulations suggest each protomer contains a putative ion conduction pore; single-point mutation M207A greatly increases membrane pressure-activated currents; each subunit binds one cholesterol molecule; wild-type hTACAN structure corresponds to a closed state.","method":"Single-particle cryo-EM, molecular dynamics simulation, site-directed mutagenesis (M207A) with patch-clamp electrophysiology, cholesterol binding identified from structure","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with mutagenesis showing gain-of-function, single lab, mutant behavior may not reflect WT function","pmids":["35235791"],"is_preprint":false},{"year":2022,"finding":"TACAN forms a complex with PKD2 in native renal cell lines; TACAN inhibits PKD2 channel activity (single-channel conductance and open probability) through direct physical interaction; TACAN N-terminal S1-containing fragment interacts with PKD2 C-terminal fragment (N580-L700) and TACAN C-terminal S6-containing fragment interacts with PKD2 N-terminal fragment; the PKD2-TACAN complex, but not PKD2 alone, confers mechanosensitivity; TACAN aggravates PKD2-dependent tail curvature and pronephric cysts in larval zebrafish.","method":"Co-immunoprecipitation in renal cell lines, two-electrode voltage clamp in Xenopus oocytes, patch-clamp in mammalian cells (single-channel conductance and open probability), fragment interaction mapping, zebrafish in vivo model","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus in vitro electrophysiology plus in vivo zebrafish validation, reciprocal fragment interaction mapping, multiple orthogonal methods","pmids":["36420836"],"is_preprint":false},{"year":2022,"finding":"Parkin interacts with TACAN (TMEM120A) and knockdown of Parkin increases membrane trafficking of TACAN in sensory neurons; hen egg lysozyme increases Parkin expression (via NRF1-P300-mediated histone acetylation of the prkn promoter) and thereby decreases TACAN membrane trafficking, reducing static mechanical allodynia.","method":"Co-immunoprecipitation (Parkin-TACAN interaction), siRNA knockdown of Parkin with membrane trafficking assay, in vivo behavioral pain assays, chromatin immunoprecipitation (NRF1-P300 interaction at prkn promoter)","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, functional membrane trafficking assay, in vivo behavioral validation, multiple methods but single lab","pmids":["35985504"],"is_preprint":false},{"year":2023,"finding":"Nuclear localization of TMEM120A is required for its role in regulating chemotherapy sensitivity in colorectal cancer; nuclear TMEM120A sustains nuclear CoA levels, which influences nuclear acetyl-CoA levels and histone acetylation; direct inhibition of histone acetylation recapitulates TMEM120A depletion phenotype (increased chemosensitivity).","method":"CRISPR/Cas9 knockout, lentiviral overexpression of TMEM120A derivatives, cell fractionation, acid extraction of histones + western blot for histone acetylation, MTS cell viability assay","journal":"Cancer chemotherapy and pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO plus domain localization variants plus orthogonal pharmacological rescue, single lab","pmids":["37728615"],"is_preprint":false},{"year":2025,"finding":"TMEM120A is an ER-resident CoA-binding protein; it interacts with ER-localized acyl-CoA synthetases ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and channeling into the ER, facilitating fatty acid re-esterification and lipid cycling during lipolysis; by relieving acyl-CoA-mediated feedback inhibition of lipolysis, TMEM120A enhances lipid turnover and protects against ER stress; adipocyte-specific deletion impairs lipolysis-induced energy expenditure and exacerbates inflammation and metabolic dysfunction under high-fat diet.","method":"Co-immunoprecipitation (TMEM120A-ACSL1/ACSL3 interaction), ER localization by subcellular fractionation/imaging, adipocyte-specific Tmem120a knockout mice, metabolic phenotyping, lipolysis and acyl-CoA synthesis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying binding partners, ER localization with functional consequence, adipocyte-specific KO with multiple metabolic readouts, multiple orthogonal methods in single study","pmids":["41423633"],"is_preprint":false},{"year":2023,"finding":"In C. elegans, tmem-120 (sole TMEM120A/B ortholog) is expressed in germline, embryos, and spermatheca; loss-of-function causes deformed germline, maternal sterility, and reduced brood size; loss of tmem-120 suppresses (alleviates) the brood size reduction and defective sperm navigation in pezo-1 (PIEZO ortholog) mutants, indicating a genetic epistatic interaction where tmem-120 acts as a negative regulator of pezo-1 function in reproduction.","method":"Genetic loss-of-function (full-length deletion), auxin-inducible degradation system for tissue-specific depletion, in vivo live imaging, double-mutant genetic epistasis analysis","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double-mutant analysis and tissue-specific depletion, single lab, C. elegans ortholog","pmids":["38051962"],"is_preprint":false}],"current_model":"TMEM120A is a dimeric ER/nuclear envelope transmembrane protein structurally homologous to ELOVL fatty acid elongases that binds coenzyme A (CoA) in a deep transmembrane pocket; it functions as an ER CoA-handling protein that interacts with ACSL1/ACSL3 to promote acyl-CoA synthesis and fatty acid re-esterification, and its nuclear pool regulates nuclear CoA/acetyl-CoA levels and histone acetylation; it is required for adipocyte differentiation by organizing the fat-cell genome at the nuclear periphery; it negatively modulates PIEZO2 mechanosensitive channel activity through an epistatic interaction and inhibits PKD2 channel function via direct physical interaction; it promotes innate antiviral signaling by interacting with STING and facilitating its ER-to-ERGIC translocation; although originally proposed to be a mechanosensitive ion channel (TACAN), subsequent independent structural and electrophysiological studies failed to confirm intrinsic ion channel activity."},"narrative":{"mechanistic_narrative":"TMEM120A is an ER and nuclear-envelope transmembrane protein that functions in lipid and coenzyme A (CoA) metabolism rather than as the mechanosensitive ion channel it was originally proposed to be [PMID:34374645, PMID:34374644, PMID:34409941]. Convergent cryo-EM structures define a tightly packed homodimer in which each protomer forms a six-helix transmembrane α-barrel that binds a CoA molecule in a deep pocket through a conserved central tryptophan, with an architecture homologous to the fatty acid elongase ELOVL7 [PMID:34374645, PMID:34374644, PMID:34409941]. As an ER-resident CoA-binding protein, TMEM120A interacts with the acyl-CoA synthetases ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and fatty acid re-esterification, sustaining lipid cycling during lipolysis and protecting against ER stress [PMID:41423633]. At the nuclear periphery it organizes the adipocyte genome and is required for adipocyte differentiation; its adipocyte-specific loss repositions metabolic genes, suppresses lipid metabolism programs, induces myogenic genes, and produces a lipodystrophy resembling human FPLD2 [PMID:26024229, PMID:35027552]. Its nuclear pool further sustains nuclear CoA and acetyl-CoA levels to support histone acetylation, influencing chemotherapy sensitivity in colorectal cancer [PMID:37728615]. Independently, TMEM120A acts as a negative modulator of mechanotransduction channels, decreasing PIEZO2 current amplitude and raising its activation threshold and inhibiting PKD2 channel activity through direct physical interaction [PMID:35819364, PMID:36420836]. It also promotes innate antiviral signaling by binding STING and facilitating its ER-to-ERGIC translocation, enhancing TBK1/IRF3 phosphorylation and interferon-stimulated gene expression [PMID:35013224]. Although early work reported intrinsic mechanosensitive channel activity, multiple independent structural and electrophysiological studies established that purified TMEM120A does not form a bona fide ion channel [PMID:34374644, PMID:34409941].","teleology":[{"year":2015,"claim":"Established the first cellular role for TMEM120A by placing it at the nuclear envelope and showing it is required for fat-cell differentiation, framing it as a nuclear-periphery protein with a metabolic function.","evidence":"siRNA knockdown in 3T3-L1 cells with qPCR of differentiation markers, lipid staining/CARS microscopy, and subcellular localization","pmids":["26024229"],"confidence":"Medium","gaps":["Molecular mechanism linking nuclear-envelope localization to differentiation gene expression not defined","No biochemical activity assigned","Single cell-line model"]},{"year":2020,"claim":"Proposed TMEM120A (TACAN) as an intrinsic mechanosensitive ion channel underlying nociceptor mechanotransduction, raising the central question of whether the protein conducts ions.","evidence":"Heterologous expression, purification and lipid reconstitution, nociceptor-specific inducible knockout with behavior and patch-clamp","pmids":["32084332"],"confidence":"Medium","gaps":["Channel activity not structurally substantiated","Reconstitution conduction could reflect artifact","Contested by subsequent independent groups"]},{"year":2021,"claim":"Resolved the protein's true biochemical identity: independent cryo-EM structures showed a dimeric ELOVL-like fatty acid elongase fold with a bound CoA cofactor and no ion channel pore, directly refuting the channel model.","evidence":"Single-particle cryo-EM (CoA-bound and apo), native/MS CoA identification, mutagenesis of the CoA-binding tryptophan, and patch-clamp/reconstitution electrophysiology across three labs","pmids":["34374645","34374644","34409941"],"confidence":"High","gaps":["Catalytic or transport function of the CoA pocket not directly demonstrated","Physiological consequence of apo-vs-CoA conformational switch unknown"]},{"year":2022,"claim":"Reframed TMEM120A as a modulator rather than effector of mechanotransduction, showing it specifically dampens PIEZO2 and inhibits PKD2 channel activity through physical interaction.","evidence":"Heterologous co-expression and reciprocal siRNA patch-clamp for PIEZO2; Co-IP, two-electrode/single-channel electrophysiology, fragment mapping, and zebrafish model for PKD2","pmids":["35819364","36420836"],"confidence":"High","gaps":["Structural basis of PIEZO2 modulation not resolved","Whether CoA binding is required for channel modulation unknown","Endogenous tissue relevance of PKD2 inhibition incompletely defined"]},{"year":2022,"claim":"Identified an unexpected immune function, showing TMEM120A binds STING and drives its ER-to-ERGIC trafficking to potentiate antiviral interferon signaling.","evidence":"Genome-wide overexpression screen, Co-IP, subcellular localization assays, knockout MEFs, and TBK1/IRF3 phospho-readouts","pmids":["35013224"],"confidence":"High","gaps":["Mechanism by which TMEM120A promotes STING translocation unclear","Link between CoA/lipid function and STING trafficking not established"]},{"year":2022,"claim":"Extended the negative-regulator role to a conserved reproductive context, showing the C. elegans ortholog genetically antagonizes the PIEZO ortholog pezo-1.","evidence":"Loss-of-function deletion, auxin-inducible degradation, live imaging, and double-mutant epistasis in C. elegans","pmids":["38051962"],"confidence":"Medium","gaps":["Direct physical interaction with PIEZO not shown in worm","Molecular mechanism of antagonism unresolved"]},{"year":2022,"claim":"Established the in vivo physiological importance of the nuclear-periphery function, linking TMEM120A loss to genome misorganization and a lipodystrophy phenotype mirroring human FPLD2.","evidence":"Adipocyte-specific knockout mice with 3D genome organization analysis, RNA-seq, metabolic phenotyping, and FPLD2 patient cell comparison","pmids":["35027552"],"confidence":"High","gaps":["Mechanism connecting CoA-binding biochemistry to spatial genome organization unknown","Whether genome repositioning is a direct or downstream effect unclear"]},{"year":2023,"claim":"Connected TMEM120A's CoA function to chromatin regulation, showing its nuclear pool sustains nuclear CoA/acetyl-CoA and histone acetylation to set chemotherapy sensitivity.","evidence":"CRISPR knockout, localization-variant overexpression, histone acid extraction/western blot, and pharmacological acetylation inhibition in colorectal cancer cells","pmids":["37728615"],"confidence":"Medium","gaps":["Direct measurement of TMEM120A-dependent acetyl-CoA flux not shown","Single cancer-cell context"]},{"year":2025,"claim":"Provided the unifying biochemical mechanism, showing ER-resident TMEM120A partners with ACSL1/ACSL3 to drive acyl-CoA synthesis, fatty acid re-esterification, and lipid cycling during lipolysis.","evidence":"Co-IP of ACSL1/ACSL3, ER localization, adipocyte-specific knockout mice, and lipolysis/acyl-CoA synthesis and metabolic assays","pmids":["41423633"],"confidence":"High","gaps":["Whether TMEM120A is catalytic or a CoA/acyl-CoA carrier/scaffold not resolved","Structural basis of ACSL interaction unknown"]},{"year":null,"claim":"How a single CoA-binding ELOVL-like fold reconciles its distinct roles in ER lipid metabolism, nuclear genome organization, channel modulation, and STING trafficking remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No demonstration that CoA binding is mechanistically required for the channel-modulation, genome-organization, or STING functions","No enzymatic activity directly assigned to the CoA pocket","Relationship between ER and nuclear-envelope pools not delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,9]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[3,5,12]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7,12]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,11]}],"complexes":[],"partners":["ACSL1","ACSL3","PIEZO2","PKD2","STING","PARKIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BXJ8","full_name":"Transmembrane protein 120A","aliases":["Protein TACAN","Transmembrane protein induced by tumor necrosis factor alpha"],"length_aa":343,"mass_kda":40.6,"function":"Multifunctional protein involved in mechanosensation, and plays an essential role in lipid metabolism and adipocyte differentiation (PubMed:26024229, PubMed:36420836). May function as a potential ion channel involved in sensing mechanical stimuli (PubMed:35235791). Mediates the mechanosensitivity of the PKD2-TMEM120A channel complex through direct physical interaction (PubMed:36420836). TMEM120A seems to affect mechanosensation by inhibiting PIEZO2 channels, possibly by altering cellular lipid content (By similarity). TMEM120A is structurally similar to a lipid-modifying enzyme, ELOVL7, and contains a bound coenzyme A molecule, which suggests it might function as an enzyme in lipid metabolism (PubMed:34374645, PubMed:34409941, PubMed:34465718). Additionally, implicated in innate immune response against Zika virus. Acts as a key activator of the antiviral signaling involving STING1 (PubMed:35013224)","subcellular_location":"Cell membrane; Nucleus inner membrane; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q9BXJ8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM120A","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":381,"dependency_fraction":0.0026246719160104987},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM120A","total_profiled":1310},"omim":[{"mim_id":"616551","title":"TRANSMEMBRANE PROTEIN 120B; TMEM120B","url":"https://www.omim.org/entry/616551"},{"mim_id":"616550","title":"TRANSMEMBRANE PROTEIN 120A; TMEM120A","url":"https://www.omim.org/entry/616550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM120A"},"hgnc":{"alias_symbol":["TMPIT","NET29","TACAN"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXJ8","domains":[{"cath_id":"-","chopping":"123-258_268-336","consensus_level":"medium","plddt":91.4524,"start":123,"end":336}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXJ8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXJ8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXJ8-F1-predicted_aligned_error_v6.png","plddt_mean":89.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM120A","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM120A"},"sequence":{"accession":"Q9BXJ8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXJ8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXJ8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXJ8"}},"corpus_meta":[{"pmid":"32084332","id":"PMC_32084332","title":"TACAN Is an Ion Channel Involved in Sensing Mechanical Pain.","date":"2020","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/32084332","citation_count":110,"is_preprint":false},{"pmid":"26024229","id":"PMC_26024229","title":"TMEM120A and B: Nuclear Envelope Transmembrane Proteins Important for Adipocyte Differentiation.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26024229","citation_count":61,"is_preprint":false},{"pmid":"35027552","id":"PMC_35027552","title":"Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35027552","citation_count":41,"is_preprint":false},{"pmid":"34374645","id":"PMC_34374645","title":"TMEM120A is a coenzyme A-binding membrane protein with structural similarities to ELOVL fatty acid elongase.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34374645","citation_count":31,"is_preprint":false},{"pmid":"35819364","id":"PMC_35819364","title":"TMEM120A/TACAN inhibits mechanically activated PIEZO2 channels.","date":"2022","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35819364","citation_count":29,"is_preprint":false},{"pmid":"35013224","id":"PMC_35013224","title":"Gain-of-function genetic screening identifies the antiviral function of TMEM120A via STING activation.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35013224","citation_count":28,"is_preprint":false},{"pmid":"34374644","id":"PMC_34374644","title":"Analysis of the mechanosensor channel functionality of TACAN.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34374644","citation_count":27,"is_preprint":false},{"pmid":"34409941","id":"PMC_34409941","title":"TMEM120A contains a specific coenzyme A-binding site and might not mediate poking- or stretch-induced channel activities in cells.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34409941","citation_count":23,"is_preprint":false},{"pmid":"33232830","id":"PMC_33232830","title":"Involvement of TACAN, a Mechanotransducing Ion Channel, in Inflammatory But Not Neuropathic Hyperalgesia in the Rat.","date":"2020","source":"The journal of pain","url":"https://pubmed.ncbi.nlm.nih.gov/33232830","citation_count":18,"is_preprint":false},{"pmid":"35235791","id":"PMC_35235791","title":"Cryo-EM structure of the human TACAN in a closed state.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35235791","citation_count":15,"is_preprint":false},{"pmid":"37523628","id":"PMC_37523628","title":"TMEM120A/TACAN: A putative regulator of ion channels, mechanosensation, and lipid metabolism.","date":"2023","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/37523628","citation_count":9,"is_preprint":false},{"pmid":"36420836","id":"PMC_36420836","title":"Regulation of PKD2 channel function by TACAN.","date":"2022","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/36420836","citation_count":7,"is_preprint":false},{"pmid":"36088852","id":"PMC_36088852","title":"Upregulation of TACAN in the trigeminal ganglion affects pain transduction in acute pulpitis.","date":"2022","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/36088852","citation_count":7,"is_preprint":false},{"pmid":"37728615","id":"PMC_37728615","title":"TMEM120A-mediated regulation of chemotherapy sensitivity in colorectal cancer cells.","date":"2023","source":"Cancer chemotherapy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37728615","citation_count":4,"is_preprint":false},{"pmid":"35419854","id":"PMC_35419854","title":"The curious case of TMEM120A: Mechanosensor, fat regulator, or antiviral defender?","date":"2022","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35419854","citation_count":3,"is_preprint":false},{"pmid":"35985504","id":"PMC_35985504","title":"Hen Egg Lysozyme Alleviates Static Mechanical Pain Via NRF1-Parkin-TACAN Signaling Axis in Sensory Neurons.","date":"2022","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35985504","citation_count":3,"is_preprint":false},{"pmid":"38051962","id":"PMC_38051962","title":"Transmembrane protein 120A (TMEM-120A/TACAN) coordinates with PIEZO channel during Caenorhabditis elegans reproductive regulation.","date":"2023","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/38051962","citation_count":2,"is_preprint":false},{"pmid":"41423633","id":"PMC_41423633","title":"TMEM120A maintains adipose tissue lipid homeostasis through ER CoA channeling.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41423633","citation_count":1,"is_preprint":false},{"pmid":"38444242","id":"PMC_38444242","title":"Direct single-molecule detection of CoA-SH and ATP by the membrane proteins TMEM120A and TMEM120B.","date":"2024","source":"Nanoscale","url":"https://pubmed.ncbi.nlm.nih.gov/38444242","citation_count":1,"is_preprint":false},{"pmid":"37649457","id":"PMC_37649457","title":"The expression and distribution of TACAN in human and rat bladders.","date":"2023","source":"Lower urinary tract symptoms","url":"https://pubmed.ncbi.nlm.nih.gov/37649457","citation_count":0,"is_preprint":false},{"pmid":"42184262","id":"PMC_42184262","title":"Biolayer Interferometry for Investigating Membrane Protein-Inhibitor Binding: TACAN Mutant and GsMTx4 As a Model System.","date":"2026","source":"Journal of visualized experiments : JoVE","url":"https://pubmed.ncbi.nlm.nih.gov/42184262","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11148,"output_tokens":4093,"usd":0.04742,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12065,"output_tokens":3738,"usd":0.076887,"stage2_stop_reason":"end_turn"},"total_usd":0.124307,"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\": 2020,\n      \"finding\": \"TACAN (TMEM120A) is expressed in a subset of nociceptors; heterologous expression increases mechanically evoked currents in cell lines; purification and reconstitution in synthetic lipids generates a functional ion channel; nociceptor-specific inducible knockout decreases mechanosensitivity and reduces behavioral responses to painful mechanical stimuli but not thermal or touch stimuli.\",\n      \"method\": \"Heterologous expression in cell lines, protein purification + lipid reconstitution, nociceptor-specific inducible knockout with behavioral assays and patch-clamp electrophysiology\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — reconstitution and KO with defined phenotype in single lab; ion channel activity subsequently contested by multiple independent groups\",\n      \"pmids\": [\"32084332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TMEM120A localizes to the nuclear envelope and is required for adipocyte differentiation; knockdown of TMEM120A alters expression of adipocyte differentiation genes (Gata3, Fasn, Glut4, Pparg, Adipoq) and reduces lipid accumulation in 3T3-L1 cells.\",\n      \"method\": \"siRNA knockdown in 3T3-L1 cells, qPCR for differentiation markers, Oil Red O staining and CARS microscopy for lipid accumulation, nuclear envelope localization by subcellular fractionation/microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype and multiple orthogonal readouts (gene expression, lipid staining, CARS) in single lab\",\n      \"pmids\": [\"26024229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Adipocyte-specific knockout of Tmem120a disrupts fat genome organisation (repositioning of genes, enhancers, and miRNA loci between nuclear periphery and interior), broadly suppresses lipid metabolism pathway gene expression, induces myogenic gene expression, and causes a lipodystrophy syndrome in mice resembling human FPLD2 with insulin resistance and metabolic defects.\",\n      \"method\": \"Adipocyte-specific knockout mice, 3D genome organisation analysis, RNA-seq, metabolic phenotyping, comparison with FPLD2 patient cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — adipocyte-specific KO with multiple orthogonal methods (genome organisation, transcriptomics, metabolic phenotyping) and validation in human patient cells\",\n      \"pmids\": [\"35027552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of human TMEM120A reveals a tightly packed dimer with N-terminal coiled-coil domain and C-terminal transmembrane domain (6 TMs forming an α-barrel); a coenzyme A (CoA) molecule is bound in a deep pocket within the TMD; structural homology to ELOVL fatty acid elongases; no clear structural features of an ion channel pore.\",\n      \"method\": \"Single-particle cryo-EM structure determination, CoA ligand identification by mass spectrometry (companion paper Niu et al.)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent cryo-EM structures from three separate labs (Xue et al., Niu et al., Rong et al.) all converge on same dimeric architecture and CoA-binding site\",\n      \"pmids\": [\"34374645\", \"34374644\", \"34409941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TACAN (TMEM120A) does not exhibit mechanosensitive ion channel activity; at high protein concentrations, reconstituted TACAN produces heterogeneous conduction levels inconsistent with a bona fide channel and most consistent with lipid bilayer disruption; cryo-EM structure shows each protomer contains a CoA cofactor (confirmed by mass spectrometry) and is structurally related to fatty acid elongase ELOVL7.\",\n      \"method\": \"Cellular patch-clamp recording, membrane reconstitution electrophysiology, single-particle cryo-EM, native mass spectrometry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple rigorous methods (patch-clamp, reconstitution, cryo-EM, MS) in a single study; negative ion channel result replicated across multiple independent labs\",\n      \"pmids\": [\"34374644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMEM120A expression alone is not sufficient to mediate poking- or stretch-induced currents in cells; cryo-EM structures reveal symmetrical homodimer with six membrane-spanning helices per monomer and a CoA molecule bound in a deep cavity via specific interactions with nearby residues; mutation of a central tryptophan involved in CoA binding dramatically reduces CoA binding affinity; TMEM120A adopts distinct conformations in CoA-bound vs. apo states.\",\n      \"method\": \"Patch-clamp electrophysiology (poking and stretch), single-particle cryo-EM (CoA-bound and apo states), site-directed mutagenesis of CoA-binding residue with binding affinity measurement\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus mutagenesis of binding residue plus functional electrophysiology in single rigorous study\",\n      \"pmids\": [\"34409941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM120A co-expression specifically decreases amplitudes of mechanically activated PIEZO2 currents and increases their activation threshold in heterologous cells; TMEM120A did not inhibit PIEZO1 or TREK1; TMEM120A alone did not generate mechanically activated currents above background; siRNA knockdown of Tmem120a in mouse DRG neurons increased rapidly adapting mechanically activated current amplitudes and decreased their activation thresholds; Tmem120a and Piezo2 expression overlap in DRG neurons.\",\n      \"method\": \"Heterologous co-expression with patch-clamp electrophysiology, siRNA knockdown in primary DRG neurons with patch-clamp, in situ expression analysis\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function electrophysiology in both heterologous cells and primary neurons with specificity controls (PIEZO1, TREK1 not affected)\",\n      \"pmids\": [\"35819364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM120A overexpression inhibits Zika virus (ZIKV) replication; TMEM120A interacts with STING and promotes STING translocation from the ER to ERGIC; this enhances phosphorylation of downstream TBK1 and IRF3, resulting in expression of antiviral cytokines and interferon-stimulated genes; antiviral activity is STING-dependent.\",\n      \"method\": \"Genome-wide overexpression screen, Co-immunoprecipitation, subcellular fractionation/localization assay, TMEM120A knockdown and Tmem120a knockout (MEFs), phospho-western blot for TBK1/IRF3, cytokine/ISG expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP for interaction, localization assay for STING trafficking, KO confirmation in MEFs, pathway readouts (TBK1/IRF3 phosphorylation, ISGs), multiple orthogonal methods in single study\",\n      \"pmids\": [\"35013224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of human TACAN shows each protomer has a transmembrane globular domain (6 helices) and intracellular domain (2 helices); molecular dynamics simulations suggest each protomer contains a putative ion conduction pore; single-point mutation M207A greatly increases membrane pressure-activated currents; each subunit binds one cholesterol molecule; wild-type hTACAN structure corresponds to a closed state.\",\n      \"method\": \"Single-particle cryo-EM, molecular dynamics simulation, site-directed mutagenesis (M207A) with patch-clamp electrophysiology, cholesterol binding identified from structure\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with mutagenesis showing gain-of-function, single lab, mutant behavior may not reflect WT function\",\n      \"pmids\": [\"35235791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TACAN forms a complex with PKD2 in native renal cell lines; TACAN inhibits PKD2 channel activity (single-channel conductance and open probability) through direct physical interaction; TACAN N-terminal S1-containing fragment interacts with PKD2 C-terminal fragment (N580-L700) and TACAN C-terminal S6-containing fragment interacts with PKD2 N-terminal fragment; the PKD2-TACAN complex, but not PKD2 alone, confers mechanosensitivity; TACAN aggravates PKD2-dependent tail curvature and pronephric cysts in larval zebrafish.\",\n      \"method\": \"Co-immunoprecipitation in renal cell lines, two-electrode voltage clamp in Xenopus oocytes, patch-clamp in mammalian cells (single-channel conductance and open probability), fragment interaction mapping, zebrafish in vivo model\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus in vitro electrophysiology plus in vivo zebrafish validation, reciprocal fragment interaction mapping, multiple orthogonal methods\",\n      \"pmids\": [\"36420836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Parkin interacts with TACAN (TMEM120A) and knockdown of Parkin increases membrane trafficking of TACAN in sensory neurons; hen egg lysozyme increases Parkin expression (via NRF1-P300-mediated histone acetylation of the prkn promoter) and thereby decreases TACAN membrane trafficking, reducing static mechanical allodynia.\",\n      \"method\": \"Co-immunoprecipitation (Parkin-TACAN interaction), siRNA knockdown of Parkin with membrane trafficking assay, in vivo behavioral pain assays, chromatin immunoprecipitation (NRF1-P300 interaction at prkn promoter)\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, functional membrane trafficking assay, in vivo behavioral validation, multiple methods but single lab\",\n      \"pmids\": [\"35985504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear localization of TMEM120A is required for its role in regulating chemotherapy sensitivity in colorectal cancer; nuclear TMEM120A sustains nuclear CoA levels, which influences nuclear acetyl-CoA levels and histone acetylation; direct inhibition of histone acetylation recapitulates TMEM120A depletion phenotype (increased chemosensitivity).\",\n      \"method\": \"CRISPR/Cas9 knockout, lentiviral overexpression of TMEM120A derivatives, cell fractionation, acid extraction of histones + western blot for histone acetylation, MTS cell viability assay\",\n      \"journal\": \"Cancer chemotherapy and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO plus domain localization variants plus orthogonal pharmacological rescue, single lab\",\n      \"pmids\": [\"37728615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM120A is an ER-resident CoA-binding protein; it interacts with ER-localized acyl-CoA synthetases ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and channeling into the ER, facilitating fatty acid re-esterification and lipid cycling during lipolysis; by relieving acyl-CoA-mediated feedback inhibition of lipolysis, TMEM120A enhances lipid turnover and protects against ER stress; adipocyte-specific deletion impairs lipolysis-induced energy expenditure and exacerbates inflammation and metabolic dysfunction under high-fat diet.\",\n      \"method\": \"Co-immunoprecipitation (TMEM120A-ACSL1/ACSL3 interaction), ER localization by subcellular fractionation/imaging, adipocyte-specific Tmem120a knockout mice, metabolic phenotyping, lipolysis and acyl-CoA synthesis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying binding partners, ER localization with functional consequence, adipocyte-specific KO with multiple metabolic readouts, multiple orthogonal methods in single study\",\n      \"pmids\": [\"41423633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, tmem-120 (sole TMEM120A/B ortholog) is expressed in germline, embryos, and spermatheca; loss-of-function causes deformed germline, maternal sterility, and reduced brood size; loss of tmem-120 suppresses (alleviates) the brood size reduction and defective sperm navigation in pezo-1 (PIEZO ortholog) mutants, indicating a genetic epistatic interaction where tmem-120 acts as a negative regulator of pezo-1 function in reproduction.\",\n      \"method\": \"Genetic loss-of-function (full-length deletion), auxin-inducible degradation system for tissue-specific depletion, in vivo live imaging, double-mutant genetic epistasis analysis\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double-mutant analysis and tissue-specific depletion, single lab, C. elegans ortholog\",\n      \"pmids\": [\"38051962\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM120A is a dimeric ER/nuclear envelope transmembrane protein structurally homologous to ELOVL fatty acid elongases that binds coenzyme A (CoA) in a deep transmembrane pocket; it functions as an ER CoA-handling protein that interacts with ACSL1/ACSL3 to promote acyl-CoA synthesis and fatty acid re-esterification, and its nuclear pool regulates nuclear CoA/acetyl-CoA levels and histone acetylation; it is required for adipocyte differentiation by organizing the fat-cell genome at the nuclear periphery; it negatively modulates PIEZO2 mechanosensitive channel activity through an epistatic interaction and inhibits PKD2 channel function via direct physical interaction; it promotes innate antiviral signaling by interacting with STING and facilitating its ER-to-ERGIC translocation; although originally proposed to be a mechanosensitive ion channel (TACAN), subsequent independent structural and electrophysiological studies failed to confirm intrinsic ion channel activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM120A is an ER and nuclear-envelope transmembrane protein that functions in lipid and coenzyme A (CoA) metabolism rather than as the mechanosensitive ion channel it was originally proposed to be [#3, #4]. Convergent cryo-EM structures define a tightly packed homodimer in which each protomer forms a six-helix transmembrane α-barrel that binds a CoA molecule in a deep pocket through a conserved central tryptophan, with an architecture homologous to the fatty acid elongase ELOVL7 [#3, #5]. As an ER-resident CoA-binding protein, TMEM120A interacts with the acyl-CoA synthetases ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and fatty acid re-esterification, sustaining lipid cycling during lipolysis and protecting against ER stress [#12]. At the nuclear periphery it organizes the adipocyte genome and is required for adipocyte differentiation; its adipocyte-specific loss repositions metabolic genes, suppresses lipid metabolism programs, induces myogenic genes, and produces a lipodystrophy resembling human FPLD2 [#1, #2]. Its nuclear pool further sustains nuclear CoA and acetyl-CoA levels to support histone acetylation, influencing chemotherapy sensitivity in colorectal cancer [#11]. Independently, TMEM120A acts as a negative modulator of mechanotransduction channels, decreasing PIEZO2 current amplitude and raising its activation threshold and inhibiting PKD2 channel activity through direct physical interaction [#6, #9]. It also promotes innate antiviral signaling by binding STING and facilitating its ER-to-ERGIC translocation, enhancing TBK1/IRF3 phosphorylation and interferon-stimulated gene expression [#7]. Although early work reported intrinsic mechanosensitive channel activity, multiple independent structural and electrophysiological studies established that purified TMEM120A does not form a bona fide ion channel [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the first cellular role for TMEM120A by placing it at the nuclear envelope and showing it is required for fat-cell differentiation, framing it as a nuclear-periphery protein with a metabolic function.\",\n      \"evidence\": \"siRNA knockdown in 3T3-L1 cells with qPCR of differentiation markers, lipid staining/CARS microscopy, and subcellular localization\",\n      \"pmids\": [\"26024229\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism linking nuclear-envelope localization to differentiation gene expression not defined\", \"No biochemical activity assigned\", \"Single cell-line model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Proposed TMEM120A (TACAN) as an intrinsic mechanosensitive ion channel underlying nociceptor mechanotransduction, raising the central question of whether the protein conducts ions.\",\n      \"evidence\": \"Heterologous expression, purification and lipid reconstitution, nociceptor-specific inducible knockout with behavior and patch-clamp\",\n      \"pmids\": [\"32084332\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Channel activity not structurally substantiated\", \"Reconstitution conduction could reflect artifact\", \"Contested by subsequent independent groups\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the protein's true biochemical identity: independent cryo-EM structures showed a dimeric ELOVL-like fatty acid elongase fold with a bound CoA cofactor and no ion channel pore, directly refuting the channel model.\",\n      \"evidence\": \"Single-particle cryo-EM (CoA-bound and apo), native/MS CoA identification, mutagenesis of the CoA-binding tryptophan, and patch-clamp/reconstitution electrophysiology across three labs\",\n      \"pmids\": [\"34374645\", \"34374644\", \"34409941\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Catalytic or transport function of the CoA pocket not directly demonstrated\", \"Physiological consequence of apo-vs-CoA conformational switch unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reframed TMEM120A as a modulator rather than effector of mechanotransduction, showing it specifically dampens PIEZO2 and inhibits PKD2 channel activity through physical interaction.\",\n      \"evidence\": \"Heterologous co-expression and reciprocal siRNA patch-clamp for PIEZO2; Co-IP, two-electrode/single-channel electrophysiology, fragment mapping, and zebrafish model for PKD2\",\n      \"pmids\": [\"35819364\", \"36420836\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of PIEZO2 modulation not resolved\", \"Whether CoA binding is required for channel modulation unknown\", \"Endogenous tissue relevance of PKD2 inhibition incompletely defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified an unexpected immune function, showing TMEM120A binds STING and drives its ER-to-ERGIC trafficking to potentiate antiviral interferon signaling.\",\n      \"evidence\": \"Genome-wide overexpression screen, Co-IP, subcellular localization assays, knockout MEFs, and TBK1/IRF3 phospho-readouts\",\n      \"pmids\": [\"35013224\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which TMEM120A promotes STING translocation unclear\", \"Link between CoA/lipid function and STING trafficking not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the negative-regulator role to a conserved reproductive context, showing the C. elegans ortholog genetically antagonizes the PIEZO ortholog pezo-1.\",\n      \"evidence\": \"Loss-of-function deletion, auxin-inducible degradation, live imaging, and double-mutant epistasis in C. elegans\",\n      \"pmids\": [\"38051962\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct physical interaction with PIEZO not shown in worm\", \"Molecular mechanism of antagonism unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the in vivo physiological importance of the nuclear-periphery function, linking TMEM120A loss to genome misorganization and a lipodystrophy phenotype mirroring human FPLD2.\",\n      \"evidence\": \"Adipocyte-specific knockout mice with 3D genome organization analysis, RNA-seq, metabolic phenotyping, and FPLD2 patient cell comparison\",\n      \"pmids\": [\"35027552\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism connecting CoA-binding biochemistry to spatial genome organization unknown\", \"Whether genome repositioning is a direct or downstream effect unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected TMEM120A's CoA function to chromatin regulation, showing its nuclear pool sustains nuclear CoA/acetyl-CoA and histone acetylation to set chemotherapy sensitivity.\",\n      \"evidence\": \"CRISPR knockout, localization-variant overexpression, histone acid extraction/western blot, and pharmacological acetylation inhibition in colorectal cancer cells\",\n      \"pmids\": [\"37728615\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct measurement of TMEM120A-dependent acetyl-CoA flux not shown\", \"Single cancer-cell context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the unifying biochemical mechanism, showing ER-resident TMEM120A partners with ACSL1/ACSL3 to drive acyl-CoA synthesis, fatty acid re-esterification, and lipid cycling during lipolysis.\",\n      \"evidence\": \"Co-IP of ACSL1/ACSL3, ER localization, adipocyte-specific knockout mice, and lipolysis/acyl-CoA synthesis and metabolic assays\",\n      \"pmids\": [\"41423633\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether TMEM120A is catalytic or a CoA/acyl-CoA carrier/scaffold not resolved\", \"Structural basis of ACSL interaction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single CoA-binding ELOVL-like fold reconciles its distinct roles in ER lipid metabolism, nuclear genome organization, channel modulation, and STING trafficking remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No demonstration that CoA binding is mechanistically required for the channel-modulation, genome-organization, or STING functions\", \"No enzymatic activity directly assigned to the CoA pocket\", \"Relationship between ER and nuclear-envelope pools not delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [3, 5, 12]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ACSL1\", \"ACSL3\", \"PIEZO2\", \"PKD2\", \"STING\", \"Parkin\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}