{"gene":"THRSP","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2014,"finding":"Spot14 (THRSP) directly enhances FASN catalytic activity: recombinant FASN catalysis increased 1.4-fold and C14:0 yield was enhanced 4-fold in vitro upon addition of purified Spot14; add-back of Spot14 to Spot14-null cytosolic lysates partially restored native FASN activity that was 1.6-fold lower than controls.","method":"In vitro reconstitution assay using recombinant FASN with purified Spot14, and crude cytosolic lysate activity assays with 13C fatty acid product quantification","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant proteins plus add-back rescue in lysates; multiple orthogonal methods in a single rigorous study","pmids":["24771867"],"is_preprint":false},{"year":2013,"finding":"The Spot14/Mig12 heterocomplex binds purified human ACC2, sequesters its polymerization (blocking citrate-induced filamentous polymer nucleation), and restrains its enzymatic (carboxylase) activity; the oligo-heterocomplex form only partially inhibited, identifying the full heterocomplex as the designated inhibitor.","method":"Atomic force microscopy nanoscale protein topography mapping of protein-protein interactions between purified recombinant Spot14/Mig12 and ACC2; functional enzymatic activity assays","journal":"Journal of molecular recognition : JMR","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified human proteins, AFM structural imaging, and enzymatic activity assays; multiple orthogonal methods in a single study","pmids":["24277613"],"is_preprint":false},{"year":2009,"finding":"Thrsp null mice exhibit marked deficiencies in de novo lipogenesis specifically in the lactating mammary gland, establishing a required role for Thrsp in mammary gland lipogenesis in vivo.","method":"Thrsp knockout mouse (Thrsp(tm1cnm)) phenotypic analysis including body composition and glucose tolerance measurements","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined cellular phenotype in mammary gland; replicated across backcross generations","pmids":["19356628"],"is_preprint":false},{"year":2022,"finding":"In human adipocytes, THRSP is induced by insulin in a PI3K-dependent manner (both mRNA and protein); THRSP silencing impairs mitochondrial respiration and fatty acid oxidation, and decreases hexosylceramide concentrations, placing THRSP upstream of mitochondrial function and sphingolipid metabolism in adipocytes.","method":"siRNA silencing in SGBS adipocytes, Seahorse mitochondrial respiration assay, radiolabeled oleate/glucose oxidation and uptake, lipidomic analysis, transcriptomic analysis; in vivo euglycemic insulin clamp with adipose biopsies","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple orthogonal functional readouts (respiration, lipidome, transcriptome) plus in vivo human validation; single lab but comprehensive methods","pmids":["35715726"],"is_preprint":false},{"year":2011,"finding":"ChREBP (carbohydrate response element binding protein) binds the Thrsp gene promoter in rat jejunum, and feeding resistant starch reduces both ChREBP binding and acetylation of histones H3 and H4 at the Thrsp gene, mechanistically linking these epigenetic/transcriptional events to reduced Thrsp expression.","method":"Chromatin immunoprecipitation (ChIP) for ChREBP binding and histone acetylation at the Thrsp gene locus; qRT-PCR and western blot for mRNA/protein","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP demonstrating direct transcription factor binding and histone modifications at the locus; single lab, single study","pmids":["21244091"],"is_preprint":false},{"year":2000,"finding":"NF-Y transcription factor binds the inverted CCAAT-element at position -100 of the rat Spot14 promoter and is required for basal promoter activity, as demonstrated by EMSA and in vitro transcription/translation.","method":"Electrophoretic mobility shift assay (EMSA) and in vitro transcription/translation","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding demonstrated by EMSA with functional link to promoter activity; single lab, single study","pmids":["10830504"],"is_preprint":false},{"year":2021,"finding":"THRSP knockdown in HCC cells increases cell growth, migration, and invasion, while THRSP overexpression suppresses tumorigenesis in vivo and in vitro; mechanistically, THRSP inhibits epithelial-to-mesenchymal transition through the ERK/ZEB1 signaling pathway.","method":"Lentiviral overexpression and shRNA knockdown in HCC cell lines; transwell and wound healing migration/invasion assays; western blot for ERK and ZEB1; in vivo xenograft","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss- and gain-of-function with defined signaling pathway placement (ERK/ZEB1); single lab with multiple assays but pathway inference based on correlative western blots","pmids":["34093825"],"is_preprint":false},{"year":2001,"finding":"THRP (THRSP) mRNA expression is specifically upregulated during the early (but not late) phase of LTP in rat dentate gyrus; antisense oligonucleotide knockdown of THRP before (but not after) tetanic stimulation prevented LTP induction, and NMDA receptor blockade prevented both LTP and THRP induction, placing THRP downstream of NMDA receptor activation and in the early phase of LTP.","method":"PCR differential display, quantitative RT-PCR, in situ hybridization, THRP antisense oligonucleotide treatment, MK801 NMDA receptor blockade, electrophysiological LTP recording in vivo","journal":"Hippocampus","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via antisense knockdown with defined temporal window; multiple orthogonal methods (antisense, pharmacological blockade, in situ hybridization); single lab","pmids":["11811657"],"is_preprint":false},{"year":2003,"finding":"Exogenous THRP (THRSP) expression in PC12 neuronal cells induces cell death (predominantly necrosis) and cell cycle arrest; T3 (thyroid hormone) treatment of PC12 cells induces THRP mRNA in a dose-dependent manner and reduces cell number, suggesting THRP mediates TH-induced cytotoxicity. Co-expression with wild-type or kinase-dead c-Abl did not alter THRP-induced cell death.","method":"Transfection of THRP expression construct in PC12 cells; TUNEL, propidium iodide/Hoechst staining; 3H-thymidine incorporation; qRT-PCR for THRP mRNA","journal":"Experimental brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function with multiple cell viability readouts; single lab; c-Abl interaction tested and found negative (no modulation)","pmids":["12698219"],"is_preprint":false},{"year":2004,"finding":"Exogenous THRP (THRSP) expression in primary embryonic rat neurons causes increased cell death; T3 treatment induces THRP mRNA and reduces neuronal cell number, establishing THRP as a mediator of thyroid hormone-induced neuronal cytotoxicity. Co-transfection with wild-type c-Abl did not alter THRP's effect on neuronal survival.","method":"Transfection of THRP expression construct in primary rat embryonic neurons; propidium iodide staining; LDH release assay; G418 selection survival assay; qRT-PCR","journal":"Experimental brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function in primary neurons with multiple cell death readouts; replicates findings from PC12 study in a more physiologically relevant cell type; single lab","pmids":["15490139"],"is_preprint":false},{"year":2016,"finding":"Overexpression of THRSP in goat mammary epithelial cells upregulates FASN, SCD1, DGAT2, and GPAM expression, and increases triacylglycerol concentration and concentrations of C12:0 and C14:0 (medium-chain fatty acids), while downregulating CD36 and having no effect on ACACA or SREBF1.","method":"Overexpression of THRSP in primary goat mammary epithelial cells; qRT-PCR for lipogenic gene expression; triglyceride and fatty acid content measurement","journal":"Journal of dairy science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function in primary cells with defined gene expression and biochemical readouts; single lab, no rescue or KO complement","pmids":["26851858"],"is_preprint":false},{"year":2018,"finding":"THRSP overexpression specifically in the striatum of mice leads to an inattentive phenotype (impaired novel-object recognition and Y-maze performance) without hyperactivity or impulsivity, and is accompanied by upregulation of dopamine transporter, tyrosine hydroxylase, and dopamine D1 and D2 receptor gene expression; methylphenidate normalized attention deficits and dopamine-related gene expression.","method":"Transgenic THRSP overexpressing mice; behavioral tests (novel-object recognition, Y-maze, open-field, cliff-avoidance, delay-discounting); qRT-PCR; western blot; methylphenidate pharmacological rescue","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function mouse model with multiple orthogonal behavioral and molecular readouts plus pharmacological validation; single lab","pmids":["30138648"],"is_preprint":false},{"year":2025,"finding":"Thrsp (Spot-14) silencing in brown/beige adipocytes upregulates Mid1ip1 (Spot-14R) expression and reduces thermogenic gene expression in brown and beige but not white adipocytes; Thrsp expression is increased by thyroid hormone T3 in brown/beige but decreased in white adipocytes, demonstrating cell-type-specific transcriptional regulation of metabolic and thermogenic pathways.","method":"siRNA silencing of Thrsp in EB5 (brown), EB7 (beige), and F442A (white) adipocyte cell lines; qRT-PCR for lipogenic and thermogenic gene expression; T3 treatment","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single gene silencing with gene expression readouts; single lab, no protein-level or biochemical mechanistic follow-up","pmids":["40317955"],"is_preprint":false},{"year":2024,"finding":"THRSP silencing in mouse mesenchymal stem cells reduces lipid droplet formation and downregulates key adipogenesis regulators (LPL, FABP4, PLIN1, CIDEC) and ER stress marker ATF6, as well as SCD1, LIPE, DGAT1, and AGPAT2, implicating THRSP in ER stress and PPAR signaling pathways that regulate lipid synthesis.","method":"THRSP gene silencing in mouse mesenchymal stem cells; transcriptomic and proteomic analysis; lipid droplet staining; RT-qPCR validation","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function with omics readouts; pathway placement is correlative without direct mechanistic validation; single lab","pmids":["39766829"],"is_preprint":false},{"year":2021,"finding":"miR-195 directly targets the 3' UTR of THRSP mRNA in buffalo adipocytes (validated by dual-luciferase reporter assay), reducing THRSP expression and inhibiting lipid accumulation, placing THRSP as a downstream effector of miR-195 in adipocyte lipid metabolism.","method":"Dual-luciferase reporter gene assay with miR-195 and THRSP 3' UTR; miR-195 overexpression in primary adipocytes; lipid accumulation measurement","journal":"Frontiers in genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — direct 3' UTR targeting validated by luciferase assay in a non-human (buffalo) system; single lab, no rescue of THRSP to confirm specificity","pmids":["35003205"],"is_preprint":false}],"current_model":"THRSP (Spot14) is a nuclear lipogenic protein that directly enhances FASN catalytic activity (increasing medium-chain fatty acid yield) and, as a heterocomplex with its paralog Mig12, inhibits ACC2 polymerization and enzymatic activity; it is transcriptionally activated by thyroid hormone, insulin (via PI3K), carbohydrate/glucose, and ChREBP binding to its promoter, and functionally required for de novo lipogenesis in mammary gland, liver, and adipose tissue, while also regulating mitochondrial function, sphingolipid metabolism, and dopaminergic pathways in the striatum."},"narrative":{"mechanistic_narrative":"THRSP (Spot14) is a nuclear lipogenic protein that acts as a direct regulator of fatty acid synthesis enzymes and is required for de novo lipogenesis in vivo [PMID:24771867, PMID:19356628]. It directly enhances FASN catalytic activity, increasing medium-chain fatty acid (C14:0) yield in reconstitution assays, with add-back of purified Spot14 rescuing the diminished FASN activity of Spot14-null lysates [PMID:24771867]. As a heterocomplex with its paralog Mig12, THRSP binds ACC2, blocks its citrate-induced filamentous polymerization, and restrains its carboxylase activity, with the full heterocomplex serving as the designated inhibitor [PMID:24277613]. Genetically, Thrsp is required for de novo lipogenesis in the lactating mammary gland [PMID:19356628], and its overexpression in mammary epithelial cells upregulates lipogenic genes (FASN, SCD1, DGAT2, GPAM) and raises triacylglycerol and medium-chain fatty acid content [PMID:26851858]. In adipocytes THRSP is induced by insulin via PI3K and supports mitochondrial respiration, fatty acid oxidation, and sphingolipid (hexosylceramide) homeostasis [PMID:35715726]. THRSP expression is controlled by carbohydrate/glucose signaling through ChREBP binding and histone acetylation at its promoter [PMID:21244091] and by NF-Y binding at an inverted CCAAT element required for basal promoter activity [PMID:10830504]. Beyond lipogenesis, THRSP has neural roles: it is induced during the early phase of NMDA-receptor-dependent long-term potentiation and is required for LTP induction [PMID:11811657], and its striatal overexpression produces an inattentive phenotype with altered dopamine-pathway gene expression that is normalized by methylphenidate [PMID:30138648].","teleology":[{"year":2000,"claim":"Established how the Spot14 promoter achieves basal activity, identifying a defined cis-element and trans-factor controlling its expression.","evidence":"EMSA and in vitro transcription/translation showing NF-Y binding at the inverted CCAAT element at -100 of the rat Spot14 promoter","pmids":["10830504"],"confidence":"Medium","gaps":["Does not address hormone- or nutrient-responsive regulation","Single promoter context in rat"]},{"year":2001,"claim":"Placed THRSP in neural plasticity by showing it is an NMDA-receptor-dependent early-phase LTP gene required for LTP induction.","evidence":"Antisense knockdown, MK801 NMDA blockade, in situ hybridization, and in vivo LTP recording in rat dentate gyrus","pmids":["11811657"],"confidence":"Medium","gaps":["Molecular mechanism downstream of THRSP in LTP unknown","No link to its lipogenic function"]},{"year":2003,"claim":"Tested whether THRSP mediates thyroid hormone effects in neurons, showing it drives cell death and links T3 to cytotoxicity.","evidence":"THRP overexpression in PC12 cells with TUNEL, PI/Hoechst, thymidine incorporation, and c-Abl co-expression controls","pmids":["12698219"],"confidence":"Medium","gaps":["Mechanism of cell death not resolved","c-Abl interaction tested negative","Cell-line context only"]},{"year":2004,"claim":"Extended the neuronal cytotoxicity finding to primary neurons, confirming THRSP as a mediator of thyroid hormone-induced neuronal death.","evidence":"THRP overexpression in primary rat embryonic neurons with PI staining, LDH release, and survival assays","pmids":["15490139"],"confidence":"Medium","gaps":["Pathway linking THRSP to death not defined","Physiological relevance of overexpression unclear"]},{"year":2009,"claim":"Provided in vivo proof that THRSP is required for de novo lipogenesis, defining a tissue-specific physiological role.","evidence":"Thrsp knockout mouse phenotyping showing mammary gland lipogenesis deficits during lactation","pmids":["19356628"],"confidence":"High","gaps":["Molecular mechanism not addressed in this study","Restricted to mammary phenotype readouts"]},{"year":2011,"claim":"Identified carbohydrate-responsive transcriptional control of Thrsp, linking diet to its expression via ChREBP and histone acetylation.","evidence":"ChIP for ChREBP binding and H3/H4 acetylation at the Thrsp locus in rat jejunum with resistant starch feeding","pmids":["21244091"],"confidence":"Medium","gaps":["Single tissue and dietary intervention","Functional consequence on lipogenesis not directly measured"]},{"year":2013,"claim":"Resolved a direct biochemical mechanism: the Spot14/Mig12 heterocomplex inhibits ACC2 by blocking polymerization and carboxylase activity.","evidence":"AFM topography and enzymatic assays with purified recombinant Spot14/Mig12 and human ACC2","pmids":["24277613"],"confidence":"High","gaps":["In vivo relevance of the heterocomplex not demonstrated","Stoichiometry/structure of full complex incompletely defined"]},{"year":2014,"claim":"Established that THRSP directly enhances FASN activity and medium-chain fatty acid output, defining its second enzymatic regulatory target.","evidence":"In vitro reconstitution with recombinant FASN plus purified Spot14 and add-back rescue in Spot14-null lysates with 13C product quantification","pmids":["24771867"],"confidence":"High","gaps":["Structural basis of FASN activation unknown","Whether FASN and ACC2 regulation occur simultaneously unresolved"]},{"year":2016,"claim":"Connected THRSP to a broader lipogenic gene program in mammary cells, showing it drives medium-chain fatty acid and triacylglycerol synthesis.","evidence":"THRSP overexpression in goat mammary epithelial cells with qRT-PCR and lipid content measurement","pmids":["26851858"],"confidence":"Medium","gaps":["Direct vs indirect effects on gene expression not distinguished","No knockout complement"]},{"year":2018,"claim":"Revealed a striatal role for THRSP in attention and dopamine signaling, beyond its metabolic functions.","evidence":"Striatal-overexpressing transgenic mice with behavioral testing, expression profiling, and methylphenidate rescue","pmids":["30138648"],"confidence":"Medium","gaps":["Molecular link between THRSP and dopamine genes unknown","Overexpression model may not reflect endogenous role"]},{"year":2021,"claim":"Extended THRSP function to tumor biology, placing it as a suppressor of EMT in hepatocellular carcinoma.","evidence":"Lentiviral overexpression/shRNA in HCC lines, migration/invasion assays, ERK/ZEB1 western blots, and xenografts","pmids":["34093825"],"confidence":"Medium","gaps":["ERK/ZEB1 placement is correlative","Connection to lipogenic activity not established"]},{"year":2022,"claim":"Defined THRSP as an insulin/PI3K-induced regulator of adipocyte mitochondrial function and sphingolipid metabolism in humans.","evidence":"siRNA silencing in SGBS adipocytes with Seahorse respiration, oxidation assays, lipidomics, transcriptomics, and in vivo insulin clamp","pmids":["35715726"],"confidence":"High","gaps":["Direct molecular targets in mitochondria not identified","Mechanism linking THRSP to hexosylceramide unknown"]},{"year":2025,"claim":"Showed cell-type-specific transcriptional control of thermogenic and lipogenic programs by Thrsp across adipocyte subtypes.","evidence":"siRNA silencing and T3 treatment in brown, beige, and white adipocyte cell lines with qRT-PCR","pmids":["40317955"],"confidence":"Low","gaps":["Gene-expression-only readouts without protein or biochemical validation","Mechanism of Mid1ip1 induction unknown"]},{"year":null,"claim":"How THRSP coordinates its direct enzymatic regulation of FASN and ACC2 with its diverse downstream roles in mitochondrial, sphingolipid, neuronal, and dopaminergic pathways remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of THRSP bound to FASN or ACC2","Mechanism connecting lipogenic activity to neural and dopamine phenotypes unknown","Whether THRSP functions enzymatically or solely as a regulatory adaptor in vivo unsettled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2,3,10]}],"complexes":["Spot14/Mig12 heterocomplex"],"partners":["FASN","ACC2","MID1IP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92748","full_name":"Thyroid hormone-inducible hepatic protein","aliases":["Spot 14 protein","S14","SPOT14"],"length_aa":146,"mass_kda":16.6,"function":"Plays a role in the regulation of lipogenesis, especially in lactating mammary gland. Important for the biosynthesis of triglycerides with medium-length fatty acid chains. May modulate lipogenesis by interacting with MID1IP1 and preventing its interaction with ACACA (By similarity). May function as transcriptional coactivator. May modulate the transcription factor activity of THRB","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q92748/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/THRSP","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/THRSP","total_profiled":1310},"omim":[{"mim_id":"601926","title":"THYROID HORMONE-RESPONSIVE PROTEIN; THRSP","url":"https://www.omim.org/entry/601926"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":197.2},{"tissue":"liver","ntpm":411.6}],"url":"https://www.proteinatlas.org/search/THRSP"},"hgnc":{"alias_symbol":["SPOT14","Lpgp","S14","THRP"],"prev_symbol":["LPGP1"]},"alphafold":{"accession":"Q92748","domains":[{"cath_id":"-","chopping":"9-42_53-77_107-146","consensus_level":"medium","plddt":87.5192,"start":9,"end":146}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92748","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92748-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92748-F1-predicted_aligned_error_v6.png","plddt_mean":74.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=THRSP","jax_strain_url":"https://www.jax.org/strain/search?query=THRSP"},"sequence":{"accession":"Q92748","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92748.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92748/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92748"}},"corpus_meta":[{"pmid":"6092074","id":"PMC_6092074","title":"Activation 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uncovers a deletion that likely inactivates the THRSP gene.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/39604663","citation_count":4,"is_preprint":false},{"pmid":"10830504","id":"PMC_10830504","title":"Dependence of rat spot14 promoter activity on NF-Y binding to the inverted CCAAT-element at -100.","date":"2000","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10830504","citation_count":2,"is_preprint":false},{"pmid":"21095221","id":"PMC_21095221","title":"The thyroid hormone responsive protein (THRP) has a critical role in the embryogenesis of Xenopus laevis.","date":"2010","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/21095221","citation_count":1,"is_preprint":false},{"pmid":"40493342","id":"PMC_40493342","title":"Unraveling Predominantly Inattentive ADHD (ADHD-PI): Insights from Proteomic Analysis of the Striatum of Thyroid Hormone-Responsive Protein (THRSP)-Overexpressing Mice.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/40493342","citation_count":1,"is_preprint":false},{"pmid":"19273419","id":"PMC_19273419","title":"[Progresses on thyroid hormone responsive spot 14 (THRSP) gene in chickens and ducks].","date":"2009","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/19273419","citation_count":0,"is_preprint":false},{"pmid":"40317955","id":"PMC_40317955","title":"Spot-14 and its paralog Spot-14R regulate expression of metabolic and thermogenic pathway genes in murine brown and beige adipocytes.","date":"2025","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/40317955","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17612,"output_tokens":3892,"usd":0.055608,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11697,"output_tokens":3661,"usd":0.075005,"stage2_stop_reason":"end_turn"},"total_usd":0.130613,"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\": 2014,\n      \"finding\": \"Spot14 (THRSP) directly enhances FASN catalytic activity: recombinant FASN catalysis increased 1.4-fold and C14:0 yield was enhanced 4-fold in vitro upon addition of purified Spot14; add-back of Spot14 to Spot14-null cytosolic lysates partially restored native FASN activity that was 1.6-fold lower than controls.\",\n      \"method\": \"In vitro reconstitution assay using recombinant FASN with purified Spot14, and crude cytosolic lysate activity assays with 13C fatty acid product quantification\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant proteins plus add-back rescue in lysates; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"24771867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The Spot14/Mig12 heterocomplex binds purified human ACC2, sequesters its polymerization (blocking citrate-induced filamentous polymer nucleation), and restrains its enzymatic (carboxylase) activity; the oligo-heterocomplex form only partially inhibited, identifying the full heterocomplex as the designated inhibitor.\",\n      \"method\": \"Atomic force microscopy nanoscale protein topography mapping of protein-protein interactions between purified recombinant Spot14/Mig12 and ACC2; functional enzymatic activity assays\",\n      \"journal\": \"Journal of molecular recognition : JMR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified human proteins, AFM structural imaging, and enzymatic activity assays; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"24277613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Thrsp null mice exhibit marked deficiencies in de novo lipogenesis specifically in the lactating mammary gland, establishing a required role for Thrsp in mammary gland lipogenesis in vivo.\",\n      \"method\": \"Thrsp knockout mouse (Thrsp(tm1cnm)) phenotypic analysis including body composition and glucose tolerance measurements\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined cellular phenotype in mammary gland; replicated across backcross generations\",\n      \"pmids\": [\"19356628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In human adipocytes, THRSP is induced by insulin in a PI3K-dependent manner (both mRNA and protein); THRSP silencing impairs mitochondrial respiration and fatty acid oxidation, and decreases hexosylceramide concentrations, placing THRSP upstream of mitochondrial function and sphingolipid metabolism in adipocytes.\",\n      \"method\": \"siRNA silencing in SGBS adipocytes, Seahorse mitochondrial respiration assay, radiolabeled oleate/glucose oxidation and uptake, lipidomic analysis, transcriptomic analysis; in vivo euglycemic insulin clamp with adipose biopsies\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple orthogonal functional readouts (respiration, lipidome, transcriptome) plus in vivo human validation; single lab but comprehensive methods\",\n      \"pmids\": [\"35715726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ChREBP (carbohydrate response element binding protein) binds the Thrsp gene promoter in rat jejunum, and feeding resistant starch reduces both ChREBP binding and acetylation of histones H3 and H4 at the Thrsp gene, mechanistically linking these epigenetic/transcriptional events to reduced Thrsp expression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for ChREBP binding and histone acetylation at the Thrsp gene locus; qRT-PCR and western blot for mRNA/protein\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP demonstrating direct transcription factor binding and histone modifications at the locus; single lab, single study\",\n      \"pmids\": [\"21244091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"NF-Y transcription factor binds the inverted CCAAT-element at position -100 of the rat Spot14 promoter and is required for basal promoter activity, as demonstrated by EMSA and in vitro transcription/translation.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA) and in vitro transcription/translation\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding demonstrated by EMSA with functional link to promoter activity; single lab, single study\",\n      \"pmids\": [\"10830504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"THRSP knockdown in HCC cells increases cell growth, migration, and invasion, while THRSP overexpression suppresses tumorigenesis in vivo and in vitro; mechanistically, THRSP inhibits epithelial-to-mesenchymal transition through the ERK/ZEB1 signaling pathway.\",\n      \"method\": \"Lentiviral overexpression and shRNA knockdown in HCC cell lines; transwell and wound healing migration/invasion assays; western blot for ERK and ZEB1; in vivo xenograft\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss- and gain-of-function with defined signaling pathway placement (ERK/ZEB1); single lab with multiple assays but pathway inference based on correlative western blots\",\n      \"pmids\": [\"34093825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"THRP (THRSP) mRNA expression is specifically upregulated during the early (but not late) phase of LTP in rat dentate gyrus; antisense oligonucleotide knockdown of THRP before (but not after) tetanic stimulation prevented LTP induction, and NMDA receptor blockade prevented both LTP and THRP induction, placing THRP downstream of NMDA receptor activation and in the early phase of LTP.\",\n      \"method\": \"PCR differential display, quantitative RT-PCR, in situ hybridization, THRP antisense oligonucleotide treatment, MK801 NMDA receptor blockade, electrophysiological LTP recording in vivo\",\n      \"journal\": \"Hippocampus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via antisense knockdown with defined temporal window; multiple orthogonal methods (antisense, pharmacological blockade, in situ hybridization); single lab\",\n      \"pmids\": [\"11811657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Exogenous THRP (THRSP) expression in PC12 neuronal cells induces cell death (predominantly necrosis) and cell cycle arrest; T3 (thyroid hormone) treatment of PC12 cells induces THRP mRNA in a dose-dependent manner and reduces cell number, suggesting THRP mediates TH-induced cytotoxicity. Co-expression with wild-type or kinase-dead c-Abl did not alter THRP-induced cell death.\",\n      \"method\": \"Transfection of THRP expression construct in PC12 cells; TUNEL, propidium iodide/Hoechst staining; 3H-thymidine incorporation; qRT-PCR for THRP mRNA\",\n      \"journal\": \"Experimental brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function with multiple cell viability readouts; single lab; c-Abl interaction tested and found negative (no modulation)\",\n      \"pmids\": [\"12698219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Exogenous THRP (THRSP) expression in primary embryonic rat neurons causes increased cell death; T3 treatment induces THRP mRNA and reduces neuronal cell number, establishing THRP as a mediator of thyroid hormone-induced neuronal cytotoxicity. Co-transfection with wild-type c-Abl did not alter THRP's effect on neuronal survival.\",\n      \"method\": \"Transfection of THRP expression construct in primary rat embryonic neurons; propidium iodide staining; LDH release assay; G418 selection survival assay; qRT-PCR\",\n      \"journal\": \"Experimental brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function in primary neurons with multiple cell death readouts; replicates findings from PC12 study in a more physiologically relevant cell type; single lab\",\n      \"pmids\": [\"15490139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Overexpression of THRSP in goat mammary epithelial cells upregulates FASN, SCD1, DGAT2, and GPAM expression, and increases triacylglycerol concentration and concentrations of C12:0 and C14:0 (medium-chain fatty acids), while downregulating CD36 and having no effect on ACACA or SREBF1.\",\n      \"method\": \"Overexpression of THRSP in primary goat mammary epithelial cells; qRT-PCR for lipogenic gene expression; triglyceride and fatty acid content measurement\",\n      \"journal\": \"Journal of dairy science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function in primary cells with defined gene expression and biochemical readouts; single lab, no rescue or KO complement\",\n      \"pmids\": [\"26851858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"THRSP overexpression specifically in the striatum of mice leads to an inattentive phenotype (impaired novel-object recognition and Y-maze performance) without hyperactivity or impulsivity, and is accompanied by upregulation of dopamine transporter, tyrosine hydroxylase, and dopamine D1 and D2 receptor gene expression; methylphenidate normalized attention deficits and dopamine-related gene expression.\",\n      \"method\": \"Transgenic THRSP overexpressing mice; behavioral tests (novel-object recognition, Y-maze, open-field, cliff-avoidance, delay-discounting); qRT-PCR; western blot; methylphenidate pharmacological rescue\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function mouse model with multiple orthogonal behavioral and molecular readouts plus pharmacological validation; single lab\",\n      \"pmids\": [\"30138648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Thrsp (Spot-14) silencing in brown/beige adipocytes upregulates Mid1ip1 (Spot-14R) expression and reduces thermogenic gene expression in brown and beige but not white adipocytes; Thrsp expression is increased by thyroid hormone T3 in brown/beige but decreased in white adipocytes, demonstrating cell-type-specific transcriptional regulation of metabolic and thermogenic pathways.\",\n      \"method\": \"siRNA silencing of Thrsp in EB5 (brown), EB7 (beige), and F442A (white) adipocyte cell lines; qRT-PCR for lipogenic and thermogenic gene expression; T3 treatment\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single gene silencing with gene expression readouts; single lab, no protein-level or biochemical mechanistic follow-up\",\n      \"pmids\": [\"40317955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"THRSP silencing in mouse mesenchymal stem cells reduces lipid droplet formation and downregulates key adipogenesis regulators (LPL, FABP4, PLIN1, CIDEC) and ER stress marker ATF6, as well as SCD1, LIPE, DGAT1, and AGPAT2, implicating THRSP in ER stress and PPAR signaling pathways that regulate lipid synthesis.\",\n      \"method\": \"THRSP gene silencing in mouse mesenchymal stem cells; transcriptomic and proteomic analysis; lipid droplet staining; RT-qPCR validation\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function with omics readouts; pathway placement is correlative without direct mechanistic validation; single lab\",\n      \"pmids\": [\"39766829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-195 directly targets the 3' UTR of THRSP mRNA in buffalo adipocytes (validated by dual-luciferase reporter assay), reducing THRSP expression and inhibiting lipid accumulation, placing THRSP as a downstream effector of miR-195 in adipocyte lipid metabolism.\",\n      \"method\": \"Dual-luciferase reporter gene assay with miR-195 and THRSP 3' UTR; miR-195 overexpression in primary adipocytes; lipid accumulation measurement\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct 3' UTR targeting validated by luciferase assay in a non-human (buffalo) system; single lab, no rescue of THRSP to confirm specificity\",\n      \"pmids\": [\"35003205\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THRSP (Spot14) is a nuclear lipogenic protein that directly enhances FASN catalytic activity (increasing medium-chain fatty acid yield) and, as a heterocomplex with its paralog Mig12, inhibits ACC2 polymerization and enzymatic activity; it is transcriptionally activated by thyroid hormone, insulin (via PI3K), carbohydrate/glucose, and ChREBP binding to its promoter, and functionally required for de novo lipogenesis in mammary gland, liver, and adipose tissue, while also regulating mitochondrial function, sphingolipid metabolism, and dopaminergic pathways in the striatum.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"THRSP (Spot14) is a nuclear lipogenic protein that acts as a direct regulator of fatty acid synthesis enzymes and is required for de novo lipogenesis in vivo [#0, #2]. It directly enhances FASN catalytic activity, increasing medium-chain fatty acid (C14:0) yield in reconstitution assays, with add-back of purified Spot14 rescuing the diminished FASN activity of Spot14-null lysates [#0]. As a heterocomplex with its paralog Mig12, THRSP binds ACC2, blocks its citrate-induced filamentous polymerization, and restrains its carboxylase activity, with the full heterocomplex serving as the designated inhibitor [#1]. Genetically, Thrsp is required for de novo lipogenesis in the lactating mammary gland [#2], and its overexpression in mammary epithelial cells upregulates lipogenic genes (FASN, SCD1, DGAT2, GPAM) and raises triacylglycerol and medium-chain fatty acid content [#10]. In adipocytes THRSP is induced by insulin via PI3K and supports mitochondrial respiration, fatty acid oxidation, and sphingolipid (hexosylceramide) homeostasis [#3]. THRSP expression is controlled by carbohydrate/glucose signaling through ChREBP binding and histone acetylation at its promoter [#4] and by NF-Y binding at an inverted CCAAT element required for basal promoter activity [#5]. Beyond lipogenesis, THRSP has neural roles: it is induced during the early phase of NMDA-receptor-dependent long-term potentiation and is required for LTP induction [#7], and its striatal overexpression produces an inattentive phenotype with altered dopamine-pathway gene expression that is normalized by methylphenidate [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established how the Spot14 promoter achieves basal activity, identifying a defined cis-element and trans-factor controlling its expression.\",\n      \"evidence\": \"EMSA and in vitro transcription/translation showing NF-Y binding at the inverted CCAAT element at -100 of the rat Spot14 promoter\",\n      \"pmids\": [\"10830504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address hormone- or nutrient-responsive regulation\", \"Single promoter context in rat\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placed THRSP in neural plasticity by showing it is an NMDA-receptor-dependent early-phase LTP gene required for LTP induction.\",\n      \"evidence\": \"Antisense knockdown, MK801 NMDA blockade, in situ hybridization, and in vivo LTP recording in rat dentate gyrus\",\n      \"pmids\": [\"11811657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism downstream of THRSP in LTP unknown\", \"No link to its lipogenic function\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Tested whether THRSP mediates thyroid hormone effects in neurons, showing it drives cell death and links T3 to cytotoxicity.\",\n      \"evidence\": \"THRP overexpression in PC12 cells with TUNEL, PI/Hoechst, thymidine incorporation, and c-Abl co-expression controls\",\n      \"pmids\": [\"12698219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of cell death not resolved\", \"c-Abl interaction tested negative\", \"Cell-line context only\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended the neuronal cytotoxicity finding to primary neurons, confirming THRSP as a mediator of thyroid hormone-induced neuronal death.\",\n      \"evidence\": \"THRP overexpression in primary rat embryonic neurons with PI staining, LDH release, and survival assays\",\n      \"pmids\": [\"15490139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway linking THRSP to death not defined\", \"Physiological relevance of overexpression unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided in vivo proof that THRSP is required for de novo lipogenesis, defining a tissue-specific physiological role.\",\n      \"evidence\": \"Thrsp knockout mouse phenotyping showing mammary gland lipogenesis deficits during lactation\",\n      \"pmids\": [\"19356628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism not addressed in this study\", \"Restricted to mammary phenotype readouts\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified carbohydrate-responsive transcriptional control of Thrsp, linking diet to its expression via ChREBP and histone acetylation.\",\n      \"evidence\": \"ChIP for ChREBP binding and H3/H4 acetylation at the Thrsp locus in rat jejunum with resistant starch feeding\",\n      \"pmids\": [\"21244091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tissue and dietary intervention\", \"Functional consequence on lipogenesis not directly measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved a direct biochemical mechanism: the Spot14/Mig12 heterocomplex inhibits ACC2 by blocking polymerization and carboxylase activity.\",\n      \"evidence\": \"AFM topography and enzymatic assays with purified recombinant Spot14/Mig12 and human ACC2\",\n      \"pmids\": [\"24277613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the heterocomplex not demonstrated\", \"Stoichiometry/structure of full complex incompletely defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that THRSP directly enhances FASN activity and medium-chain fatty acid output, defining its second enzymatic regulatory target.\",\n      \"evidence\": \"In vitro reconstitution with recombinant FASN plus purified Spot14 and add-back rescue in Spot14-null lysates with 13C product quantification\",\n      \"pmids\": [\"24771867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FASN activation unknown\", \"Whether FASN and ACC2 regulation occur simultaneously unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected THRSP to a broader lipogenic gene program in mammary cells, showing it drives medium-chain fatty acid and triacylglycerol synthesis.\",\n      \"evidence\": \"THRSP overexpression in goat mammary epithelial cells with qRT-PCR and lipid content measurement\",\n      \"pmids\": [\"26851858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effects on gene expression not distinguished\", \"No knockout complement\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a striatal role for THRSP in attention and dopamine signaling, beyond its metabolic functions.\",\n      \"evidence\": \"Striatal-overexpressing transgenic mice with behavioral testing, expression profiling, and methylphenidate rescue\",\n      \"pmids\": [\"30138648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between THRSP and dopamine genes unknown\", \"Overexpression model may not reflect endogenous role\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended THRSP function to tumor biology, placing it as a suppressor of EMT in hepatocellular carcinoma.\",\n      \"evidence\": \"Lentiviral overexpression/shRNA in HCC lines, migration/invasion assays, ERK/ZEB1 western blots, and xenografts\",\n      \"pmids\": [\"34093825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ERK/ZEB1 placement is correlative\", \"Connection to lipogenic activity not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined THRSP as an insulin/PI3K-induced regulator of adipocyte mitochondrial function and sphingolipid metabolism in humans.\",\n      \"evidence\": \"siRNA silencing in SGBS adipocytes with Seahorse respiration, oxidation assays, lipidomics, transcriptomics, and in vivo insulin clamp\",\n      \"pmids\": [\"35715726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular targets in mitochondria not identified\", \"Mechanism linking THRSP to hexosylceramide unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed cell-type-specific transcriptional control of thermogenic and lipogenic programs by Thrsp across adipocyte subtypes.\",\n      \"evidence\": \"siRNA silencing and T3 treatment in brown, beige, and white adipocyte cell lines with qRT-PCR\",\n      \"pmids\": [\"40317955\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Gene-expression-only readouts without protein or biochemical validation\", \"Mechanism of Mid1ip1 induction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How THRSP coordinates its direct enzymatic regulation of FASN and ACC2 with its diverse downstream roles in mitochondrial, sphingolipid, neuronal, and dopaminergic pathways remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of THRSP bound to FASN or ACC2\", \"Mechanism connecting lipogenic activity to neural and dopamine phenotypes unknown\", \"Whether THRSP functions enzymatically or solely as a regulatory adaptor in vivo unsettled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2, 3, 10]}\n    ],\n    \"complexes\": [\"Spot14/Mig12 heterocomplex\"],\n    \"partners\": [\"FASN\", \"ACC2\", \"MID1IP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}