{"gene":"CPT1C","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2008,"finding":"CPT1C localizes to the endoplasmic reticulum (not mitochondria) of neurons, with its N-terminal region responsible for ER localization. It has carnitine palmitoyltransferase activity toward palmitoyl-CoA as substrate, producing palmitoylcarnitine, but with 20–300 times lower catalytic efficiency than CPT1A.","method":"GFP-fusion overexpression and live-cell imaging, subcellular fractionation/Western blot from mouse brain, HPLC-MS acylcarnitine profiling in PC-12 cells, microsomal CPT1 activity assays with kinetic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (localization imaging, fractionation, enzymatic activity assay, MS metabolite profiling, kinetics) in a single focused study","pmids":["18192268"],"is_preprint":false},{"year":2007,"finding":"CPT1C is widely expressed in neurons throughout the CNS including hypothalamic feeding centers, where it localizes as an outer integral membrane protein of mitochondria (this localization differs from the 2008 ER finding). Ectopic over-expression of CPT1C in the hypothalamus via stereotactic adenoviral injection protects mice from high-fat diet-induced weight gain.","method":"Immunohistochemistry, mitochondrial fractionation, stereotactic adenoviral injection with body weight monitoring in mice","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization by fractionation and in vivo functional experiment, but mitochondrial localization contradicted by later ER localization paper; functional result replicated in concept","pmids":["17559810"],"is_preprint":false},{"year":2013,"finding":"CPT1C in the hypothalamus is required for the orexigenic action of ghrelin. Ghrelin signaling upregulates hypothalamic C18:0 ceramide levels in a CPT1C-dependent manner, and central ceramide synthesis inhibition blocks ghrelin-induced feeding; central ceramide administration rescues food intake in CPT1C KO mice.","method":"CPT1C knockout mouse model, intracerebroventricular drug administration (ghrelin, myriocin, ceramide), neuropeptide expression analysis (AgRP, NPY), ceramide level measurement","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus pharmacological rescue with multiple orthogonal readouts; independently positioned within established AMPK-malonyl-CoA pathway","pmids":["23493572"],"is_preprint":false},{"year":2009,"finding":"CPT1C KO mice develop more severe high-fat diet-induced insulin resistance than wild-type, attributable to elevated hepatic gluconeogenesis and decreased skeletal muscle glucose uptake, associated with reduced fatty acid oxidation in those tissues. CPT1C deletion also causes compensatory elevation of hypothalamic CPT1A and CPT1B expression and activity, partly induced by elevated plasma NEFA.","method":"CPT1C knockout mouse model, glucose/insulin tolerance tests, hepatic gluconeogenesis assays, skeletal muscle glucose uptake, gene expression and activity assays in liver and muscle","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple defined metabolic phenotypic readouts and tissue-level mechanistic measurements","pmids":["19224198"],"is_preprint":false},{"year":2011,"finding":"The CPT1C 5′ UTR contains an upstream open reading frame (uORF) that represses translation from the main ORF. This repression is relieved by glucose deprivation and palmitate-BSA treatment, and AMPK inhibition also relieves uORF-dependent repression, linking nutrient/energy status to CPT1C translational regulation.","method":"5′ UTR/luciferase reporter constructs, sequence analysis, glucose deprivation and palmitate treatment, AMPK inhibitor treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro reporter assay with multiple stress conditions, single lab","pmids":["21961029"],"is_preprint":false},{"year":2015,"finding":"CPT1C physically interacts with AMPAR subunits GluA1 and GluA2, shares the same expression profile during neuronal maturation, and is required for normal AMPAR-mediated miniature excitatory postsynaptic currents and synaptic levels of GluA1 and GluA2. CPT1C promotes de novo synthesis (not degradation) of GluA1 post-transcriptionally and is required for mTOR-dependent GluA1 synthesis after chemical LTD and BDNF treatment.","method":"Co-immunoprecipitation, electrophysiology (mEPSC recording in CPT1C KO neurons), synaptic fractionation/Western blot, metabolic labeling for protein synthesis, CPT1C KO mouse neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, electrophysiology, protein synthesis assay, and genetic KO with multiple orthogonal methods in one study","pmids":["26338711"],"is_preprint":false},{"year":2015,"finding":"CPT1C is an interacting protein of AMPARs confirmed in heterologous expression systems; it enhances whole-cell currents of GluA1 homomeric and GluA1/GluA2 heteromeric receptors by increasing surface GluA1 receptor number, without altering AMPAR biophysical properties. CPT1C and AMPARs co-localize intracellularly (ER) but not at the plasma membrane. The palmitoylable residue C585 of GluA1 is important for CPT1C-mediated AMPAR trafficking enhancement.","method":"Co-immunoprecipitation in heterologous cells, whole-cell patch-clamp electrophysiology, surface biotinylation assay, co-localization imaging, mutagenesis of GluA1 C585","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP confirmed in heterologous system, electrophysiology, surface receptor quantification, and mutagenesis in a single study","pmids":["25698923"],"is_preprint":false},{"year":2015,"finding":"CPT1C interacts with atlastin-1 (ATL1), an ER protein encoded by a gene mutated in pure HSPs. A missense CPT1C mutation (c.109C>T, p.Cys37Arg) alters protein conformation (by NMR) and reduces the number and size of lipid droplets on overexpression; CPT1C KO neurons also show reduced lipid droplets, suggesting a role in lipid droplet biogenesis.","method":"Whole-exome sequencing, Sanger sequencing, Co-immunoprecipitation (CPT1C–atlastin-1), NMR spectroscopy, lipid droplet quantification in cells and KO neurons","journal":"JAMA neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, NMR structural perturbation, and cellular lipid droplet assay in single lab study","pmids":["25751282"],"is_preprint":false},{"year":2018,"finding":"CPT1C depalmitoylates GluA1: predicted catalytic triad residues Ser252, His470, and Asp474 are required for CPT1C's palmitoyl thioesterase (PTE) activity. Mutation of His470 (H470A) abolishes CPT1C-dependent depalmitoylation of GluA1 and eliminates the increase in GluA1 surface expression. The effect is ER-specific and isoform-specific.","method":"In silico catalytic triad prediction, site-directed mutagenesis of CPT1C (S252A, H470A, D474A), palmitoylation state assay (acyl-RAC), surface biotinylation, electrophysiology in neurons","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — active-site mutagenesis with functional readout (surface expression, palmitoylation assay), single lab","pmids":["30135643"],"is_preprint":false},{"year":2018,"finding":"CPT1C in the ventromedial hypothalamus (VMH) is necessary for leptin- and high-fat diet-induced brown adipose tissue (BAT) thermogenesis activation. CPT1C acts downstream of AMPK in the VMH: genetic inactivation of AMPK in the VMH fails to induce BAT thermogenesis and body weight loss in CPT1C KO mice. Restoration of CPT1C expression in the VMH rescues the thermogenic phenotype.","method":"CPT1C KO mice, VMH-specific AMPK knockout, intracerebroventricular leptin administration, BAT thermogenesis measurement (UCP1, temperature), VMH-specific CPT1C viral rescue","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (AMPK→CPT1C) established by double KO, viral rescue, and multiple thermogenic readouts","pmids":["30448371"],"is_preprint":false},{"year":2019,"finding":"CPT1C senses malonyl-CoA and promotes anterograde transport of late endosomes/lysosomes (LE/Lys) by interacting with the ER protein protrudin, facilitating transfer of Kinesin-1 from protrudin to LE/Lys. In cortical neurons, glucose deprivation, AMPK activation, or inhibition of malonyl-CoA synthesis decreases LE/Lys abundance at axon terminals and shortens axon length in a CPT1C-dependent manner.","method":"Co-immunoprecipitation (CPT1C–protrudin, Kinesin-1 transfer assay), live-cell imaging of LE/Lys transport in HeLa cells and mouse cortical neurons, CPT1C KD, AMPK pharmacological activation, malonyl-CoA synthesis inhibition, axon length measurement","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP interaction, live-cell transport imaging, pharmacological and genetic perturbations with defined mechanistic readouts in two cell systems","pmids":["31868590"],"is_preprint":false},{"year":2020,"finding":"CPT1C regulates GluA1 AMPAR trafficking through the PI(4)P phosphatase SAC1. Under normal malonyl-CoA levels, CPT1C inhibits SAC1 catalytic activity, supporting GluA1 surface delivery. Under low malonyl-CoA (e.g., glucose deprivation), CPT1C-dependent inhibition of SAC1 is released, SAC1 translocates to ER-TGN contact sites, depletes TGN PI(4)P, and retains GluA1 at the TGN.","method":"Metabolic stress paradigms in cortical neurons, SAC1 activity assay, PI(4)P quantification, GluA1 surface biotinylation, SAC1 localization imaging (ER-TGN contact sites), malonyl-CoA level measurement","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — enzymatic activity assay for SAC1, PI(4)P quantification, localization imaging, and trafficking assay under defined nutrient conditions with multiple orthogonal methods","pmids":["32931550"],"is_preprint":false},{"year":2018,"finding":"CPT1C overexpression in human mesenchymal stem cells (hMSCs) promotes survival under glucose deprivation by enhancing autophagy, leading to increased lipid droplets and elevated intracellular ATP. This is independent of fatty acid oxidation. Inhibition of autophagy or lipolysis completely blocks CPT1C's protective effects.","method":"CPT1C overexpression in hMSCs, cell viability assays under glucose/oxygen deprivation, FAO assay, autophagy inhibitor treatment, lipolysis inhibitor treatment, lipid droplet staining, ATP measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — OE with pharmacological inhibition of downstream pathway and multiple metabolic readouts, single lab","pmids":["29725060"],"is_preprint":false},{"year":2020,"finding":"ERRα (estrogen-related receptor α) is a transcription factor that directly activates CPT1C transcription. miR-1291 targets ERRα, thereby indirectly reducing CPT1C expression. CPT1C mediates effects of the miR-1291-ERRα axis on cancer cell proliferation and metabolism.","method":"Luciferase reporter assay (miR-1291 targeting ERRα 3′UTR), ChIP assay (ERRα binding to CPT1C promoter), RT-qPCR/Western blot, BrdU/colony formation/cell cycle assays, ATP/ROS measurements, xenograft tumor model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — ChIP and luciferase reporter for transcriptional regulation, single lab","pmids":["32641987"],"is_preprint":false},{"year":2024,"finding":"YY1 directly activates transcription of CPT1C under hypoxic conditions in pancreatic cancer cells. YY1 and CPT1C synergistically regulate cell proliferation and metabolism (ATP levels, mitochondrial membrane potential, lipid content) under hypoxia.","method":"YY1 siRNA knockdown, CRISPR/Cas9 CPT1C knockout, double-knockdown rescue experiments, luciferase reporter or ChIP (implied by 'directly activated'), cellular metabolic assays","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional activation claimed as direct, genetic double-KO epistasis, single lab","pmids":["38996932"],"is_preprint":false},{"year":2024,"finding":"CPT1C is a substrate of the APC/C ubiquitin ligase complex: CPT1C protein levels fluctuate in a cell cycle-dependent manner, peaking at the G1/S boundary, and APC/C-mediated degradation controls its abundance. Elevated CPT1C accelerates G1/S transition and promotes tumor cell proliferation in vitro and in vivo.","method":"Cell cycle synchronization, proximity ligation assay and Co-immunoprecipitation (CPT1C–APC/C), immunoblotting, flow cytometry, MTS/scratch/transwell assays, xenograft transplantation","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PLA and Co-IP for interaction, cell cycle synchronization for substrate cycling, single lab","pmids":["38783346"],"is_preprint":false},{"year":2023,"finding":"CPT1C silencing in breast cancer cells (MDA-MB-231) increases plasma membrane phospholipid saturation (increased PM rigidity), reduces doxorubicin uptake, and confers anthracycline resistance. These changes are associated with CPT1C-dependent lipidome remodeling.","method":"CPT1C siRNA silencing, LC-HRMS lipidomics of PM-enriched fractions, drug uptake assays, cell viability assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LC-MS lipidomics with functional drug resistance readout, single lab","pmids":["36674468"],"is_preprint":false},{"year":2023,"finding":"CPT1C knockdown induces cellular senescence in MDA-MB-231 cells accompanied by decreased stearate synthesis and increased oleate. Exogenous stearate inhibits proliferation, while oleate reverses CPT1C-knockdown-induced senescence. Inhibition of SCD-1 (stearoyl-CoA desaturase 1) phenocopies stearate-induced proliferation inhibition, placing CPT1C upstream of the stearate/oleate balance.","method":"13C-metabolic flux analysis, CPT1C knockdown, exogenous fatty acid supplementation, SCD-1 inhibitor treatment, senescence assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — 13C-MFA with pharmacological and genetic perturbations, single lab","pmids":["37151873"],"is_preprint":false},{"year":2025,"finding":"CPT1C in SF1 neurons of the VMH is required for early caloric intake adjustment and melanocortin system activation upon high-fat diet exposure. CPT1C deficiency in SF1 neurons elevates hypothalamic endocannabinoid (eCB) levels under both chow and HFD conditions, which is proposed to reduce VMH activation by fatty acids and impair SF1-POMC drive upon fat intake.","method":"SF1-neuron-specific CPT1C conditional knockout mice, HFD feeding experiments, melanocortin pathway activation assays, endocannabinoid level measurement in hypothalamus, metabolic gene expression in peripheral tissues","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with defined signaling readouts (melanocortin, eCB), single lab","pmids":["40268191"],"is_preprint":false},{"year":2026,"finding":"CPT1C depalmitoylates GluA1 in the nucleus accumbens; enhanced GluA1 depalmitoylation mediates chronic stress-induced depressive-like behaviors. D2-MSN-specific CPT1C knockdown prevents stress-induced depression, while CPT1C deficiency in D1-MSNs abolishes fluoxetine's behavioral and synaptic effects. CPT1C also promotes GluA1 synthesis by disinhibiting mTORC1 via targeting tuberous sclerosis complex 2 (TSC2).","method":"Cell-type-specific (D1-MSN/D2-MSN) CPT1C knockdown, GluA1 depalmitoylation assay, chronic stress mouse model, behavioral assays, mTORC1 signaling analysis (TSC2 interaction), synaptic plasticity recording","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KD with depalmitoylation assay and mTORC1 pathway dissection, single lab, not yet independently replicated","pmids":["41741705"],"is_preprint":false},{"year":2026,"finding":"Fenofibrate activates PPARα, which transcriptionally upregulates CPT1C; CPT1C mediates fenofibrate's ability to restore mitochondrial function in senescent cells. Fenofibrate cannot reverse aging in Pparα−/− mice, establishing PPARα-dependence of the CPT1C upregulation.","method":"PPARα KO mice, D-galactose aging model, SAMP8 mice, lipidomic profiling, metabolic analyses of mitochondrial function, CPT1C expression analysis","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PPARα KO genetic epistasis with metabolic functional readouts, single lab","pmids":["41765248"],"is_preprint":false},{"year":2023,"finding":"CPT1C is required for synaptic plasticity at the CA3-CA1 synapse: CPT1C KO mice show impaired long-term potentiation, reduced cortical γ oscillations, and deficits in hippocampal dendritic spine maturation, alongside motor learning, spatial memory, and habituation memory deficits.","method":"CPT1C KO mice, in vivo and ex vivo electrophysiology (LTP at CA3-CA1), cortical oscillation recording (EEG), dendritic spine morphology analysis, behavioral testing battery","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with electrophysiology and spine morphology, multiple behavioral readouts, single lab","pmids":["37309891"],"is_preprint":false}],"current_model":"CPT1C is a brain-specific ER-resident protein that senses malonyl-CoA levels to coordinate multiple neuronal functions: it acts as a low-efficiency palmitoyl thioesterase (depalmitoylating GluA1), promotes AMPAR (GluA1/GluA2) synthesis via mTORC1 and surface trafficking by inhibiting the PI(4)P phosphatase SAC1, facilitates anterograde lysosome/late-endosome transport by bridging protrudin and Kinesin-1, regulates hypothalamic ceramide and endocannabinoid metabolism to control food intake and BAT thermogenesis downstream of AMPK, and its own translation is controlled by a 5′ UTR upstream ORF that is relieved by nutrient stress; in cancer cells CPT1C modulates lipid droplet biogenesis, plasma membrane composition, and fatty acid/ceramide metabolism to support survival under metabolic stress, and its protein levels are cell-cycle-regulated by APC/C-mediated degradation."},"narrative":{"mechanistic_narrative":"CPT1C is a brain-enriched, malonyl-CoA-responsive endoplasmic reticulum protein that couples cellular energy and nutrient status to neuronal lipid signaling, synaptic receptor trafficking, and organelle transport [PMID:18192268, PMID:31868590]. Although it retains weak carnitine palmitoyltransferase activity toward palmitoyl-CoA, its catalytic efficiency is 20–300 times lower than CPT1A, and it localizes to the ER rather than mitochondria, distinguishing it functionally from canonical CPT1 isoforms [PMID:18192268]. CPT1C operates as a low-efficiency palmitoyl thioesterase, using a Ser252/His470/Asp474 catalytic triad to depalmitoylate the AMPA receptor subunit GluA1 and thereby control its surface delivery [PMID:30135643]. It physically interacts with GluA1 and GluA2 and promotes AMPAR-mediated synaptic transmission by driving de novo, mTOR-dependent GluA1 synthesis and by enhancing surface receptor number through the palmitoylable GluA1 residue C585 [PMID:26338711, PMID:25698923]. CPT1C transduces malonyl-CoA levels into receptor trafficking decisions by inhibiting the PI(4)P phosphatase SAC1: when malonyl-CoA is high CPT1C restrains SAC1 to support GluA1 surface delivery, while glucose deprivation releases this inhibition, depletes TGN PI(4)P, and retains GluA1 intracellularly [PMID:32931550]. In parallel, CPT1C binds the ER protein protrudin to facilitate transfer of Kinesin-1 onto late endosomes/lysosomes, promoting their anterograde transport and axon elongation in a malonyl-CoA- and AMPK-dependent manner [PMID:31868590]. Consistent with these synaptic roles, CPT1C-deficient mice show impaired CA3-CA1 long-term potentiation, defective dendritic spine maturation, and learning and memory deficits [PMID:37309891]. In the hypothalamus CPT1C acts downstream of AMPK to regulate ceramide and endocannabinoid metabolism, controlling ghrelin-induced feeding and leptin/diet-induced brown adipose tissue thermogenesis [PMID:23493572, PMID:30448371, PMID:40268191]. CPT1C translation is itself gated by a 5′ UTR upstream ORF that is de-repressed by glucose deprivation, palmitate, and AMPK inhibition, embedding the protein within an energy-sensing feedback loop [PMID:21961029]. In cancer cells CPT1C is transcriptionally driven by ERRα and YY1 and remodels lipid metabolism—supporting autophagy-dependent survival under glucose deprivation, lipid droplet biogenesis, plasma-membrane lipid saturation, and the stearate/oleate balance—while its abundance is restricted by APC/C-mediated degradation across the cell cycle [PMID:29725060, PMID:32641987, PMID:38996932, PMID:38783346, PMID:36674468, PMID:37151873]. A missense CPT1C mutation (p.Cys37Arg) that perturbs protein conformation and reduces lipid droplets is linked to hereditary spastic paraplegia, consistent with its interaction with atlastin-1 [PMID:25751282].","teleology":[{"year":2007,"claim":"Establishing where CPT1C acts and whether it influences whole-body energy balance was the first question; its CNS-wide neuronal expression and the protection from diet-induced weight gain on hypothalamic overexpression positioned it as a neuronal regulator of feeding.","evidence":"Immunohistochemistry, mitochondrial fractionation, and stereotactic adenoviral overexpression with body-weight monitoring in mice","pmids":["17559810"],"confidence":"Medium","gaps":["Reported mitochondrial localization was later contradicted by ER localization","Mechanism linking CPT1C to feeding not defined","No molecular activity assigned"]},{"year":2008,"claim":"Defining the biochemical identity of CPT1C resolved its subcellular home and showed it is a poor carnitine palmitoyltransferase, implying its physiological role is not bulk fatty acid oxidation.","evidence":"GFP-fusion live imaging, brain subcellular fractionation, HPLC-MS acylcarnitine profiling, and microsomal CPT1 kinetic assays in PC-12 cells","pmids":["18192268"],"confidence":"High","gaps":["Physiological substrate and true catalytic function unresolved","Reconciliation with prior mitochondrial localization claim incomplete","No interacting partners identified"]},{"year":2009,"claim":"Whole-body knockout revealed that loss of CPT1C worsens diet-induced insulin resistance with tissue-level metabolic deficits, demonstrating a systemic metabolic function despite CNS-restricted expression.","evidence":"CPT1C KO mice with glucose/insulin tolerance tests, hepatic gluconeogenesis and muscle glucose uptake assays, and compensatory CPT1A/CPT1B expression measurement","pmids":["19224198"],"confidence":"High","gaps":["Peripheral phenotypes are indirect consequences of central deficiency","Molecular mechanism not addressed","Compensatory isoform upregulation complicates interpretation"]},{"year":2011,"claim":"Discovery of a 5′ UTR uORF that represses CPT1C translation, relieved by nutrient stress and AMPK inhibition, established that CPT1C abundance is wired to cellular energy status.","evidence":"5′ UTR luciferase reporter constructs under glucose deprivation, palmitate, and AMPK inhibitor treatment","pmids":["21961029"],"confidence":"Medium","gaps":["In vitro reporter only, single lab","Endogenous translational regulation not demonstrated","Trans-acting factors binding the uORF unknown"]},{"year":2013,"claim":"Genetic and pharmacological dissection placed CPT1C in the ghrelin-AMPK-ceramide feeding circuit, providing a mechanistic link between CPT1C and orexigenic signaling.","evidence":"CPT1C KO mice with intracerebroventricular ghrelin, ceramide-synthesis inhibitor, and ceramide rescue, plus neuropeptide and ceramide measurements","pmids":["23493572"],"confidence":"High","gaps":["How CPT1C controls ceramide levels enzymatically unclear","Direct molecular target downstream of CPT1C not identified"]},{"year":2015,"claim":"Identifying CPT1C as a physical and functional partner of AMPAR subunits established a synaptic role distinct from metabolism, showing it promotes de novo GluA1 synthesis and surface delivery without altering receptor biophysics.","evidence":"Reciprocal Co-IP, mEPSC electrophysiology in KO neurons, metabolic labeling for synthesis, surface biotinylation, and GluA1 C585 mutagenesis in neurons and heterologous cells","pmids":["26338711","25698923"],"confidence":"High","gaps":["Molecular activity of CPT1C on GluA1 not yet defined","Mechanism of mTOR-dependent synthesis enhancement unknown","Link between metabolism and AMPAR regulation unresolved"]},{"year":2015,"claim":"Linking a CPT1C missense mutation and an atlastin-1 interaction to reduced lipid droplets connected CPT1C to hereditary spastic paraplegia and to lipid droplet biogenesis.","evidence":"Whole-exome sequencing, Co-IP with atlastin-1, NMR conformational analysis of the C37R mutant, and lipid droplet quantification in cells and KO neurons","pmids":["25751282"],"confidence":"Medium","gaps":["Causality of the mutation in disease from a single family","Mechanism connecting CPT1C to lipid droplet formation unresolved","Functional role of atlastin-1 interaction undefined"]},{"year":2018,"claim":"Catalytic-triad mutagenesis assigned a palmitoyl thioesterase activity to CPT1C and showed that depalmitoylation of GluA1 underlies its trafficking effect, defining the molecular mechanism behind the AMPAR phenotype.","evidence":"In silico triad prediction, S252A/H470A/D474A mutagenesis, acyl-RAC palmitoylation assay, surface biotinylation, and electrophysiology in neurons","pmids":["30135643"],"confidence":"Medium","gaps":["Thioesterase activity demonstrated indirectly via mutants, single lab","Full substrate repertoire beyond GluA1 unknown","Relationship to weak acyltransferase activity unclear"]},{"year":2018,"claim":"VMH-specific epistasis experiments placed CPT1C downstream of AMPK in controlling brown adipose tissue thermogenesis, extending its hypothalamic role from feeding to energy expenditure.","evidence":"CPT1C KO and VMH AMPK double knockout mice, icv leptin, BAT thermogenesis readouts, and VMH-specific viral CPT1C rescue","pmids":["30448371"],"confidence":"High","gaps":["Molecular effector linking CPT1C to UCP1 induction not defined","Lipid species mediating the signal not identified"]},{"year":2019,"claim":"The protrudin-Kinesin-1 mechanism showed CPT1C acts as a malonyl-CoA sensor governing anterograde lysosome/endosome transport and axon growth, unifying its energy-sensing and trafficking functions.","evidence":"Co-IP and Kinesin-1 transfer assays, live-cell LE/Lys transport imaging in HeLa and cortical neurons, AMPK activation, malonyl-CoA inhibition, and axon length measurement","pmids":["31868590"],"confidence":"High","gaps":["Structural basis of malonyl-CoA sensing not resolved","Whether thioesterase activity is involved in transport unclear"]},{"year":2020,"claim":"Identifying SAC1 as a CPT1C-regulated PI(4)P phosphatase provided the mechanistic bridge between malonyl-CoA status and GluA1 trafficking through ER-TGN contact sites.","evidence":"Metabolic stress in cortical neurons, SAC1 activity assay, PI(4)P quantification, GluA1 surface biotinylation, SAC1 localization imaging, and malonyl-CoA measurement","pmids":["32931550"],"confidence":"High","gaps":["Direct physical regulation of SAC1 by CPT1C not structurally defined","Single lab"]},{"year":2020,"claim":"Transcriptional control of CPT1C by ERRα, modulated by miR-1291, established that CPT1C expression is regulated to support cancer cell proliferation and metabolism.","evidence":"Luciferase reporter, ChIP, expression assays, proliferation/cell-cycle/ATP/ROS readouts, and xenograft model","pmids":["32641987"],"confidence":"Medium","gaps":["Direct metabolic mechanism in tumors not dissected","Single lab","Generality across cancer types untested"]},{"year":2018,"claim":"Overexpression in mesenchymal stem cells revealed an FAO-independent, autophagy- and lipolysis-dependent survival function under glucose deprivation, expanding CPT1C beyond neurons into stress-adaptive metabolism.","evidence":"CPT1C overexpression in hMSCs, viability under glucose/oxygen deprivation, FAO assay, autophagy and lipolysis inhibitor treatment, lipid droplet and ATP measurement","pmids":["29725060"],"confidence":"Medium","gaps":["Mechanism connecting CPT1C to autophagy induction unknown","Overexpression model may not reflect endogenous role"]},{"year":2023,"claim":"Lipidomic and flux studies in breast cancer cells tied CPT1C to plasma membrane lipid saturation, drug uptake/anthracycline resistance, and the stearate/oleate balance controlling senescence, defining its lipid-remodeling role in cancer.","evidence":"CPT1C silencing, LC-HRMS lipidomics, 13C-metabolic flux analysis, drug uptake/viability assays, fatty acid supplementation, SCD-1 inhibition, and senescence assays","pmids":["36674468","37151873"],"confidence":"Medium","gaps":["Enzymatic basis of CPT1C-dependent lipid remodeling unresolved","Single cell line for each phenotype","Direct vs indirect effects on membrane composition unclear"]},{"year":2024,"claim":"Identification of CPT1C as an APC/C substrate and a YY1/hypoxia-regulated gene showed that its abundance is cell-cycle- and stress-controlled to drive tumor proliferation.","evidence":"Cell cycle synchronization, PLA and Co-IP with APC/C, YY1 knockdown and CPT1C CRISPR KO epistasis, metabolic assays, and xenograft models","pmids":["38783346","38996932"],"confidence":"Medium","gaps":["APC/C degron and adaptor specificity not mapped","Direct YY1 promoter binding inferred","Single lab for each"]},{"year":2026,"claim":"Cell-type-specific work in the nucleus accumbens connected CPT1C-mediated GluA1 depalmitoylation and mTORC1 disinhibition via TSC2 to stress-induced depressive behavior and antidepressant response, generalizing the AMPAR mechanism to behavior.","evidence":"D1/D2-MSN-specific CPT1C knockdown, GluA1 depalmitoylation assay, chronic stress model, behavioral and synaptic plasticity recording, and TSC2/mTORC1 analysis","pmids":["41741705"],"confidence":"Medium","gaps":["Not independently replicated","Mechanism of TSC2 targeting not biochemically defined","Cell-type-specific circuit logic incompletely mapped"]},{"year":null,"claim":"How CPT1C's weak acyltransferase activity, palmitoyl thioesterase activity, and malonyl-CoA sensing are integrated into a single biochemical mechanism—and what structural features underlie SAC1 inhibition, protrudin binding, and substrate recognition—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CPT1C bound to malonyl-CoA, GluA1, SAC1, or protrudin","Full physiological substrate repertoire of the thioesterase activity undefined","Whether catalytic and sensing functions are mechanistically coupled is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[10,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,10,11]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5,6,21]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,9,17]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[15]}],"complexes":[],"partners":["GRIA1","GRIA2","ATL1","ZFYVE27","SACM1L","ANKRD13","ESRRA","YY1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TCG5","full_name":"Palmitoyl thioesterase CPT1C","aliases":["Carnitine O-palmitoyltransferase 1, brain isoform","CPTI-B","Carnitine palmitoyltransferase 1C","Carnitine palmitoyltransferase I","CPT I-C"],"length_aa":803,"mass_kda":91.0,"function":"Palmitoyl thioesterase specifically expressed in the endoplasmic reticulum of neurons. Modulates the trafficking of the glutamate receptor, AMPAR, to plasma membrane through depalmitoylation of GRIA1 (PubMed:30135643). Also regulates AMPR trafficking through the regulation of SACM1L phosphatidylinositol-3-phosphatase activity by interaction in a malonyl-CoA dependent manner (By similarity). Binds malonyl-CoA and couples malonyl-CoA to ceramide levels, necessary for proper spine maturation and contributing to systemic energy homeostasis and appetite control (PubMed:16651524). Binds to palmitoyl-CoA, but does not have carnitine palmitoyltransferase 1 catalytic activity or at very low levels (PubMed:25751282, PubMed:30135643)","subcellular_location":"Cell projection, dendrite; Cell projection, axon; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q8TCG5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CPT1C","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CPT1C","total_profiled":1310},"omim":[{"mim_id":"616282","title":"SPASTIC PARAPLEGIA 73, AUTOSOMAL DOMINANT; SPG73","url":"https://www.omim.org/entry/616282"},{"mim_id":"608846","title":"CARNITINE PALMITOYLTRANSFERASE IC; CPT1C","url":"https://www.omim.org/entry/608846"},{"mim_id":"608597","title":"NEURALIZED E3 UBIQUITIN PROTEIN LIGASE 2; NEURL2","url":"https://www.omim.org/entry/608597"},{"mim_id":"601987","title":"CARNITINE PALMITOYLTRANSFERASE I, MUSCLE; CPT1B","url":"https://www.omim.org/entry/601987"},{"mim_id":"182600","title":"SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT; SPG3A","url":"https://www.omim.org/entry/182600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":26.3},{"tissue":"choroid plexus","ntpm":27.7},{"tissue":"pituitary gland","ntpm":26.9}],"url":"https://www.proteinatlas.org/search/CPT1C"},"hgnc":{"alias_symbol":["FLJ23809","CPTIC","CPT1P","CATL1"],"prev_symbol":[]},"alphafold":{"accession":"Q8TCG5","domains":[{"cath_id":"-","chopping":"53-157","consensus_level":"high","plddt":86.091,"start":53,"end":157},{"cath_id":"3.30.559.10","chopping":"178-236_542-770","consensus_level":"medium","plddt":94.6863,"start":178,"end":770},{"cath_id":"3.30.559.70","chopping":"259-541","consensus_level":"high","plddt":95.214,"start":259,"end":541}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCG5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCG5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCG5-F1-predicted_aligned_error_v6.png","plddt_mean":88.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CPT1C","jax_strain_url":"https://www.jax.org/strain/search?query=CPT1C"},"sequence":{"accession":"Q8TCG5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TCG5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TCG5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCG5"}},"corpus_meta":[{"pmid":"18192268","id":"PMC_18192268","title":"CPT1c 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It has carnitine palmitoyltransferase activity toward palmitoyl-CoA as substrate, producing palmitoylcarnitine, but with 20–300 times lower catalytic efficiency than CPT1A.\",\n      \"method\": \"GFP-fusion overexpression and live-cell imaging, subcellular fractionation/Western blot from mouse brain, HPLC-MS acylcarnitine profiling in PC-12 cells, microsomal CPT1 activity assays with kinetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (localization imaging, fractionation, enzymatic activity assay, MS metabolite profiling, kinetics) in a single focused study\",\n      \"pmids\": [\"18192268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CPT1C is widely expressed in neurons throughout the CNS including hypothalamic feeding centers, where it localizes as an outer integral membrane protein of mitochondria (this localization differs from the 2008 ER finding). Ectopic over-expression of CPT1C in the hypothalamus via stereotactic adenoviral injection protects mice from high-fat diet-induced weight gain.\",\n      \"method\": \"Immunohistochemistry, mitochondrial fractionation, stereotactic adenoviral injection with body weight monitoring in mice\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization by fractionation and in vivo functional experiment, but mitochondrial localization contradicted by later ER localization paper; functional result replicated in concept\",\n      \"pmids\": [\"17559810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CPT1C in the hypothalamus is required for the orexigenic action of ghrelin. Ghrelin signaling upregulates hypothalamic C18:0 ceramide levels in a CPT1C-dependent manner, and central ceramide synthesis inhibition blocks ghrelin-induced feeding; central ceramide administration rescues food intake in CPT1C KO mice.\",\n      \"method\": \"CPT1C knockout mouse model, intracerebroventricular drug administration (ghrelin, myriocin, ceramide), neuropeptide expression analysis (AgRP, NPY), ceramide level measurement\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus pharmacological rescue with multiple orthogonal readouts; independently positioned within established AMPK-malonyl-CoA pathway\",\n      \"pmids\": [\"23493572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CPT1C KO mice develop more severe high-fat diet-induced insulin resistance than wild-type, attributable to elevated hepatic gluconeogenesis and decreased skeletal muscle glucose uptake, associated with reduced fatty acid oxidation in those tissues. CPT1C deletion also causes compensatory elevation of hypothalamic CPT1A and CPT1B expression and activity, partly induced by elevated plasma NEFA.\",\n      \"method\": \"CPT1C knockout mouse model, glucose/insulin tolerance tests, hepatic gluconeogenesis assays, skeletal muscle glucose uptake, gene expression and activity assays in liver and muscle\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple defined metabolic phenotypic readouts and tissue-level mechanistic measurements\",\n      \"pmids\": [\"19224198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The CPT1C 5′ UTR contains an upstream open reading frame (uORF) that represses translation from the main ORF. This repression is relieved by glucose deprivation and palmitate-BSA treatment, and AMPK inhibition also relieves uORF-dependent repression, linking nutrient/energy status to CPT1C translational regulation.\",\n      \"method\": \"5′ UTR/luciferase reporter constructs, sequence analysis, glucose deprivation and palmitate treatment, AMPK inhibitor treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reporter assay with multiple stress conditions, single lab\",\n      \"pmids\": [\"21961029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CPT1C physically interacts with AMPAR subunits GluA1 and GluA2, shares the same expression profile during neuronal maturation, and is required for normal AMPAR-mediated miniature excitatory postsynaptic currents and synaptic levels of GluA1 and GluA2. CPT1C promotes de novo synthesis (not degradation) of GluA1 post-transcriptionally and is required for mTOR-dependent GluA1 synthesis after chemical LTD and BDNF treatment.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology (mEPSC recording in CPT1C KO neurons), synaptic fractionation/Western blot, metabolic labeling for protein synthesis, CPT1C KO mouse neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, electrophysiology, protein synthesis assay, and genetic KO with multiple orthogonal methods in one study\",\n      \"pmids\": [\"26338711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CPT1C is an interacting protein of AMPARs confirmed in heterologous expression systems; it enhances whole-cell currents of GluA1 homomeric and GluA1/GluA2 heteromeric receptors by increasing surface GluA1 receptor number, without altering AMPAR biophysical properties. CPT1C and AMPARs co-localize intracellularly (ER) but not at the plasma membrane. The palmitoylable residue C585 of GluA1 is important for CPT1C-mediated AMPAR trafficking enhancement.\",\n      \"method\": \"Co-immunoprecipitation in heterologous cells, whole-cell patch-clamp electrophysiology, surface biotinylation assay, co-localization imaging, mutagenesis of GluA1 C585\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP confirmed in heterologous system, electrophysiology, surface receptor quantification, and mutagenesis in a single study\",\n      \"pmids\": [\"25698923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CPT1C interacts with atlastin-1 (ATL1), an ER protein encoded by a gene mutated in pure HSPs. A missense CPT1C mutation (c.109C>T, p.Cys37Arg) alters protein conformation (by NMR) and reduces the number and size of lipid droplets on overexpression; CPT1C KO neurons also show reduced lipid droplets, suggesting a role in lipid droplet biogenesis.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, Co-immunoprecipitation (CPT1C–atlastin-1), NMR spectroscopy, lipid droplet quantification in cells and KO neurons\",\n      \"journal\": \"JAMA neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, NMR structural perturbation, and cellular lipid droplet assay in single lab study\",\n      \"pmids\": [\"25751282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CPT1C depalmitoylates GluA1: predicted catalytic triad residues Ser252, His470, and Asp474 are required for CPT1C's palmitoyl thioesterase (PTE) activity. Mutation of His470 (H470A) abolishes CPT1C-dependent depalmitoylation of GluA1 and eliminates the increase in GluA1 surface expression. The effect is ER-specific and isoform-specific.\",\n      \"method\": \"In silico catalytic triad prediction, site-directed mutagenesis of CPT1C (S252A, H470A, D474A), palmitoylation state assay (acyl-RAC), surface biotinylation, electrophysiology in neurons\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — active-site mutagenesis with functional readout (surface expression, palmitoylation assay), single lab\",\n      \"pmids\": [\"30135643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CPT1C in the ventromedial hypothalamus (VMH) is necessary for leptin- and high-fat diet-induced brown adipose tissue (BAT) thermogenesis activation. CPT1C acts downstream of AMPK in the VMH: genetic inactivation of AMPK in the VMH fails to induce BAT thermogenesis and body weight loss in CPT1C KO mice. Restoration of CPT1C expression in the VMH rescues the thermogenic phenotype.\",\n      \"method\": \"CPT1C KO mice, VMH-specific AMPK knockout, intracerebroventricular leptin administration, BAT thermogenesis measurement (UCP1, temperature), VMH-specific CPT1C viral rescue\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (AMPK→CPT1C) established by double KO, viral rescue, and multiple thermogenic readouts\",\n      \"pmids\": [\"30448371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CPT1C senses malonyl-CoA and promotes anterograde transport of late endosomes/lysosomes (LE/Lys) by interacting with the ER protein protrudin, facilitating transfer of Kinesin-1 from protrudin to LE/Lys. In cortical neurons, glucose deprivation, AMPK activation, or inhibition of malonyl-CoA synthesis decreases LE/Lys abundance at axon terminals and shortens axon length in a CPT1C-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation (CPT1C–protrudin, Kinesin-1 transfer assay), live-cell imaging of LE/Lys transport in HeLa cells and mouse cortical neurons, CPT1C KD, AMPK pharmacological activation, malonyl-CoA synthesis inhibition, axon length measurement\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP interaction, live-cell transport imaging, pharmacological and genetic perturbations with defined mechanistic readouts in two cell systems\",\n      \"pmids\": [\"31868590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CPT1C regulates GluA1 AMPAR trafficking through the PI(4)P phosphatase SAC1. Under normal malonyl-CoA levels, CPT1C inhibits SAC1 catalytic activity, supporting GluA1 surface delivery. Under low malonyl-CoA (e.g., glucose deprivation), CPT1C-dependent inhibition of SAC1 is released, SAC1 translocates to ER-TGN contact sites, depletes TGN PI(4)P, and retains GluA1 at the TGN.\",\n      \"method\": \"Metabolic stress paradigms in cortical neurons, SAC1 activity assay, PI(4)P quantification, GluA1 surface biotinylation, SAC1 localization imaging (ER-TGN contact sites), malonyl-CoA level measurement\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — enzymatic activity assay for SAC1, PI(4)P quantification, localization imaging, and trafficking assay under defined nutrient conditions with multiple orthogonal methods\",\n      \"pmids\": [\"32931550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CPT1C overexpression in human mesenchymal stem cells (hMSCs) promotes survival under glucose deprivation by enhancing autophagy, leading to increased lipid droplets and elevated intracellular ATP. This is independent of fatty acid oxidation. Inhibition of autophagy or lipolysis completely blocks CPT1C's protective effects.\",\n      \"method\": \"CPT1C overexpression in hMSCs, cell viability assays under glucose/oxygen deprivation, FAO assay, autophagy inhibitor treatment, lipolysis inhibitor treatment, lipid droplet staining, ATP measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — OE with pharmacological inhibition of downstream pathway and multiple metabolic readouts, single lab\",\n      \"pmids\": [\"29725060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERRα (estrogen-related receptor α) is a transcription factor that directly activates CPT1C transcription. miR-1291 targets ERRα, thereby indirectly reducing CPT1C expression. CPT1C mediates effects of the miR-1291-ERRα axis on cancer cell proliferation and metabolism.\",\n      \"method\": \"Luciferase reporter assay (miR-1291 targeting ERRα 3′UTR), ChIP assay (ERRα binding to CPT1C promoter), RT-qPCR/Western blot, BrdU/colony formation/cell cycle assays, ATP/ROS measurements, xenograft tumor model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP and luciferase reporter for transcriptional regulation, single lab\",\n      \"pmids\": [\"32641987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YY1 directly activates transcription of CPT1C under hypoxic conditions in pancreatic cancer cells. YY1 and CPT1C synergistically regulate cell proliferation and metabolism (ATP levels, mitochondrial membrane potential, lipid content) under hypoxia.\",\n      \"method\": \"YY1 siRNA knockdown, CRISPR/Cas9 CPT1C knockout, double-knockdown rescue experiments, luciferase reporter or ChIP (implied by 'directly activated'), cellular metabolic assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional activation claimed as direct, genetic double-KO epistasis, single lab\",\n      \"pmids\": [\"38996932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPT1C is a substrate of the APC/C ubiquitin ligase complex: CPT1C protein levels fluctuate in a cell cycle-dependent manner, peaking at the G1/S boundary, and APC/C-mediated degradation controls its abundance. Elevated CPT1C accelerates G1/S transition and promotes tumor cell proliferation in vitro and in vivo.\",\n      \"method\": \"Cell cycle synchronization, proximity ligation assay and Co-immunoprecipitation (CPT1C–APC/C), immunoblotting, flow cytometry, MTS/scratch/transwell assays, xenograft transplantation\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PLA and Co-IP for interaction, cell cycle synchronization for substrate cycling, single lab\",\n      \"pmids\": [\"38783346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1C silencing in breast cancer cells (MDA-MB-231) increases plasma membrane phospholipid saturation (increased PM rigidity), reduces doxorubicin uptake, and confers anthracycline resistance. These changes are associated with CPT1C-dependent lipidome remodeling.\",\n      \"method\": \"CPT1C siRNA silencing, LC-HRMS lipidomics of PM-enriched fractions, drug uptake assays, cell viability assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LC-MS lipidomics with functional drug resistance readout, single lab\",\n      \"pmids\": [\"36674468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1C knockdown induces cellular senescence in MDA-MB-231 cells accompanied by decreased stearate synthesis and increased oleate. Exogenous stearate inhibits proliferation, while oleate reverses CPT1C-knockdown-induced senescence. Inhibition of SCD-1 (stearoyl-CoA desaturase 1) phenocopies stearate-induced proliferation inhibition, placing CPT1C upstream of the stearate/oleate balance.\",\n      \"method\": \"13C-metabolic flux analysis, CPT1C knockdown, exogenous fatty acid supplementation, SCD-1 inhibitor treatment, senescence assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — 13C-MFA with pharmacological and genetic perturbations, single lab\",\n      \"pmids\": [\"37151873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CPT1C in SF1 neurons of the VMH is required for early caloric intake adjustment and melanocortin system activation upon high-fat diet exposure. CPT1C deficiency in SF1 neurons elevates hypothalamic endocannabinoid (eCB) levels under both chow and HFD conditions, which is proposed to reduce VMH activation by fatty acids and impair SF1-POMC drive upon fat intake.\",\n      \"method\": \"SF1-neuron-specific CPT1C conditional knockout mice, HFD feeding experiments, melanocortin pathway activation assays, endocannabinoid level measurement in hypothalamus, metabolic gene expression in peripheral tissues\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with defined signaling readouts (melanocortin, eCB), single lab\",\n      \"pmids\": [\"40268191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CPT1C depalmitoylates GluA1 in the nucleus accumbens; enhanced GluA1 depalmitoylation mediates chronic stress-induced depressive-like behaviors. D2-MSN-specific CPT1C knockdown prevents stress-induced depression, while CPT1C deficiency in D1-MSNs abolishes fluoxetine's behavioral and synaptic effects. CPT1C also promotes GluA1 synthesis by disinhibiting mTORC1 via targeting tuberous sclerosis complex 2 (TSC2).\",\n      \"method\": \"Cell-type-specific (D1-MSN/D2-MSN) CPT1C knockdown, GluA1 depalmitoylation assay, chronic stress mouse model, behavioral assays, mTORC1 signaling analysis (TSC2 interaction), synaptic plasticity recording\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KD with depalmitoylation assay and mTORC1 pathway dissection, single lab, not yet independently replicated\",\n      \"pmids\": [\"41741705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Fenofibrate activates PPARα, which transcriptionally upregulates CPT1C; CPT1C mediates fenofibrate's ability to restore mitochondrial function in senescent cells. Fenofibrate cannot reverse aging in Pparα−/− mice, establishing PPARα-dependence of the CPT1C upregulation.\",\n      \"method\": \"PPARα KO mice, D-galactose aging model, SAMP8 mice, lipidomic profiling, metabolic analyses of mitochondrial function, CPT1C expression analysis\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PPARα KO genetic epistasis with metabolic functional readouts, single lab\",\n      \"pmids\": [\"41765248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1C is required for synaptic plasticity at the CA3-CA1 synapse: CPT1C KO mice show impaired long-term potentiation, reduced cortical γ oscillations, and deficits in hippocampal dendritic spine maturation, alongside motor learning, spatial memory, and habituation memory deficits.\",\n      \"method\": \"CPT1C KO mice, in vivo and ex vivo electrophysiology (LTP at CA3-CA1), cortical oscillation recording (EEG), dendritic spine morphology analysis, behavioral testing battery\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with electrophysiology and spine morphology, multiple behavioral readouts, single lab\",\n      \"pmids\": [\"37309891\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CPT1C is a brain-specific ER-resident protein that senses malonyl-CoA levels to coordinate multiple neuronal functions: it acts as a low-efficiency palmitoyl thioesterase (depalmitoylating GluA1), promotes AMPAR (GluA1/GluA2) synthesis via mTORC1 and surface trafficking by inhibiting the PI(4)P phosphatase SAC1, facilitates anterograde lysosome/late-endosome transport by bridging protrudin and Kinesin-1, regulates hypothalamic ceramide and endocannabinoid metabolism to control food intake and BAT thermogenesis downstream of AMPK, and its own translation is controlled by a 5′ UTR upstream ORF that is relieved by nutrient stress; in cancer cells CPT1C modulates lipid droplet biogenesis, plasma membrane composition, and fatty acid/ceramide metabolism to support survival under metabolic stress, and its protein levels are cell-cycle-regulated by APC/C-mediated degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CPT1C is a brain-enriched, malonyl-CoA-responsive endoplasmic reticulum protein that couples cellular energy and nutrient status to neuronal lipid signaling, synaptic receptor trafficking, and organelle transport [#0, #10]. Although it retains weak carnitine palmitoyltransferase activity toward palmitoyl-CoA, its catalytic efficiency is 20–300 times lower than CPT1A, and it localizes to the ER rather than mitochondria, distinguishing it functionally from canonical CPT1 isoforms [#0]. CPT1C operates as a low-efficiency palmitoyl thioesterase, using a Ser252/His470/Asp474 catalytic triad to depalmitoylate the AMPA receptor subunit GluA1 and thereby control its surface delivery [#8]. It physically interacts with GluA1 and GluA2 and promotes AMPAR-mediated synaptic transmission by driving de novo, mTOR-dependent GluA1 synthesis and by enhancing surface receptor number through the palmitoylable GluA1 residue C585 [#5, #6]. CPT1C transduces malonyl-CoA levels into receptor trafficking decisions by inhibiting the PI(4)P phosphatase SAC1: when malonyl-CoA is high CPT1C restrains SAC1 to support GluA1 surface delivery, while glucose deprivation releases this inhibition, depletes TGN PI(4)P, and retains GluA1 intracellularly [#11]. In parallel, CPT1C binds the ER protein protrudin to facilitate transfer of Kinesin-1 onto late endosomes/lysosomes, promoting their anterograde transport and axon elongation in a malonyl-CoA- and AMPK-dependent manner [#10]. Consistent with these synaptic roles, CPT1C-deficient mice show impaired CA3-CA1 long-term potentiation, defective dendritic spine maturation, and learning and memory deficits [#21]. In the hypothalamus CPT1C acts downstream of AMPK to regulate ceramide and endocannabinoid metabolism, controlling ghrelin-induced feeding and leptin/diet-induced brown adipose tissue thermogenesis [#2, #9, #18]. CPT1C translation is itself gated by a 5′ UTR upstream ORF that is de-repressed by glucose deprivation, palmitate, and AMPK inhibition, embedding the protein within an energy-sensing feedback loop [#4]. In cancer cells CPT1C is transcriptionally driven by ERRα and YY1 and remodels lipid metabolism—supporting autophagy-dependent survival under glucose deprivation, lipid droplet biogenesis, plasma-membrane lipid saturation, and the stearate/oleate balance—while its abundance is restricted by APC/C-mediated degradation across the cell cycle [#12, #13, #14, #15, #16, #17]. A missense CPT1C mutation (p.Cys37Arg) that perturbs protein conformation and reduces lipid droplets is linked to hereditary spastic paraplegia, consistent with its interaction with atlastin-1 [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing where CPT1C acts and whether it influences whole-body energy balance was the first question; its CNS-wide neuronal expression and the protection from diet-induced weight gain on hypothalamic overexpression positioned it as a neuronal regulator of feeding.\",\n      \"evidence\": \"Immunohistochemistry, mitochondrial fractionation, and stereotactic adenoviral overexpression with body-weight monitoring in mice\",\n      \"pmids\": [\"17559810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reported mitochondrial localization was later contradicted by ER localization\", \"Mechanism linking CPT1C to feeding not defined\", \"No molecular activity assigned\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defining the biochemical identity of CPT1C resolved its subcellular home and showed it is a poor carnitine palmitoyltransferase, implying its physiological role is not bulk fatty acid oxidation.\",\n      \"evidence\": \"GFP-fusion live imaging, brain subcellular fractionation, HPLC-MS acylcarnitine profiling, and microsomal CPT1 kinetic assays in PC-12 cells\",\n      \"pmids\": [\"18192268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate and true catalytic function unresolved\", \"Reconciliation with prior mitochondrial localization claim incomplete\", \"No interacting partners identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Whole-body knockout revealed that loss of CPT1C worsens diet-induced insulin resistance with tissue-level metabolic deficits, demonstrating a systemic metabolic function despite CNS-restricted expression.\",\n      \"evidence\": \"CPT1C KO mice with glucose/insulin tolerance tests, hepatic gluconeogenesis and muscle glucose uptake assays, and compensatory CPT1A/CPT1B expression measurement\",\n      \"pmids\": [\"19224198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Peripheral phenotypes are indirect consequences of central deficiency\", \"Molecular mechanism not addressed\", \"Compensatory isoform upregulation complicates interpretation\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery of a 5′ UTR uORF that represses CPT1C translation, relieved by nutrient stress and AMPK inhibition, established that CPT1C abundance is wired to cellular energy status.\",\n      \"evidence\": \"5′ UTR luciferase reporter constructs under glucose deprivation, palmitate, and AMPK inhibitor treatment\",\n      \"pmids\": [\"21961029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro reporter only, single lab\", \"Endogenous translational regulation not demonstrated\", \"Trans-acting factors binding the uORF unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic and pharmacological dissection placed CPT1C in the ghrelin-AMPK-ceramide feeding circuit, providing a mechanistic link between CPT1C and orexigenic signaling.\",\n      \"evidence\": \"CPT1C KO mice with intracerebroventricular ghrelin, ceramide-synthesis inhibitor, and ceramide rescue, plus neuropeptide and ceramide measurements\",\n      \"pmids\": [\"23493572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CPT1C controls ceramide levels enzymatically unclear\", \"Direct molecular target downstream of CPT1C not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying CPT1C as a physical and functional partner of AMPAR subunits established a synaptic role distinct from metabolism, showing it promotes de novo GluA1 synthesis and surface delivery without altering receptor biophysics.\",\n      \"evidence\": \"Reciprocal Co-IP, mEPSC electrophysiology in KO neurons, metabolic labeling for synthesis, surface biotinylation, and GluA1 C585 mutagenesis in neurons and heterologous cells\",\n      \"pmids\": [\"26338711\", \"25698923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular activity of CPT1C on GluA1 not yet defined\", \"Mechanism of mTOR-dependent synthesis enhancement unknown\", \"Link between metabolism and AMPAR regulation unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linking a CPT1C missense mutation and an atlastin-1 interaction to reduced lipid droplets connected CPT1C to hereditary spastic paraplegia and to lipid droplet biogenesis.\",\n      \"evidence\": \"Whole-exome sequencing, Co-IP with atlastin-1, NMR conformational analysis of the C37R mutant, and lipid droplet quantification in cells and KO neurons\",\n      \"pmids\": [\"25751282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality of the mutation in disease from a single family\", \"Mechanism connecting CPT1C to lipid droplet formation unresolved\", \"Functional role of atlastin-1 interaction undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Catalytic-triad mutagenesis assigned a palmitoyl thioesterase activity to CPT1C and showed that depalmitoylation of GluA1 underlies its trafficking effect, defining the molecular mechanism behind the AMPAR phenotype.\",\n      \"evidence\": \"In silico triad prediction, S252A/H470A/D474A mutagenesis, acyl-RAC palmitoylation assay, surface biotinylation, and electrophysiology in neurons\",\n      \"pmids\": [\"30135643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Thioesterase activity demonstrated indirectly via mutants, single lab\", \"Full substrate repertoire beyond GluA1 unknown\", \"Relationship to weak acyltransferase activity unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"VMH-specific epistasis experiments placed CPT1C downstream of AMPK in controlling brown adipose tissue thermogenesis, extending its hypothalamic role from feeding to energy expenditure.\",\n      \"evidence\": \"CPT1C KO and VMH AMPK double knockout mice, icv leptin, BAT thermogenesis readouts, and VMH-specific viral CPT1C rescue\",\n      \"pmids\": [\"30448371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effector linking CPT1C to UCP1 induction not defined\", \"Lipid species mediating the signal not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The protrudin-Kinesin-1 mechanism showed CPT1C acts as a malonyl-CoA sensor governing anterograde lysosome/endosome transport and axon growth, unifying its energy-sensing and trafficking functions.\",\n      \"evidence\": \"Co-IP and Kinesin-1 transfer assays, live-cell LE/Lys transport imaging in HeLa and cortical neurons, AMPK activation, malonyl-CoA inhibition, and axon length measurement\",\n      \"pmids\": [\"31868590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of malonyl-CoA sensing not resolved\", \"Whether thioesterase activity is involved in transport unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying SAC1 as a CPT1C-regulated PI(4)P phosphatase provided the mechanistic bridge between malonyl-CoA status and GluA1 trafficking through ER-TGN contact sites.\",\n      \"evidence\": \"Metabolic stress in cortical neurons, SAC1 activity assay, PI(4)P quantification, GluA1 surface biotinylation, SAC1 localization imaging, and malonyl-CoA measurement\",\n      \"pmids\": [\"32931550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical regulation of SAC1 by CPT1C not structurally defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Transcriptional control of CPT1C by ERRα, modulated by miR-1291, established that CPT1C expression is regulated to support cancer cell proliferation and metabolism.\",\n      \"evidence\": \"Luciferase reporter, ChIP, expression assays, proliferation/cell-cycle/ATP/ROS readouts, and xenograft model\",\n      \"pmids\": [\"32641987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct metabolic mechanism in tumors not dissected\", \"Single lab\", \"Generality across cancer types untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Overexpression in mesenchymal stem cells revealed an FAO-independent, autophagy- and lipolysis-dependent survival function under glucose deprivation, expanding CPT1C beyond neurons into stress-adaptive metabolism.\",\n      \"evidence\": \"CPT1C overexpression in hMSCs, viability under glucose/oxygen deprivation, FAO assay, autophagy and lipolysis inhibitor treatment, lipid droplet and ATP measurement\",\n      \"pmids\": [\"29725060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CPT1C to autophagy induction unknown\", \"Overexpression model may not reflect endogenous role\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Lipidomic and flux studies in breast cancer cells tied CPT1C to plasma membrane lipid saturation, drug uptake/anthracycline resistance, and the stearate/oleate balance controlling senescence, defining its lipid-remodeling role in cancer.\",\n      \"evidence\": \"CPT1C silencing, LC-HRMS lipidomics, 13C-metabolic flux analysis, drug uptake/viability assays, fatty acid supplementation, SCD-1 inhibition, and senescence assays\",\n      \"pmids\": [\"36674468\", \"37151873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic basis of CPT1C-dependent lipid remodeling unresolved\", \"Single cell line for each phenotype\", \"Direct vs indirect effects on membrane composition unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of CPT1C as an APC/C substrate and a YY1/hypoxia-regulated gene showed that its abundance is cell-cycle- and stress-controlled to drive tumor proliferation.\",\n      \"evidence\": \"Cell cycle synchronization, PLA and Co-IP with APC/C, YY1 knockdown and CPT1C CRISPR KO epistasis, metabolic assays, and xenograft models\",\n      \"pmids\": [\"38783346\", \"38996932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"APC/C degron and adaptor specificity not mapped\", \"Direct YY1 promoter binding inferred\", \"Single lab for each\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Cell-type-specific work in the nucleus accumbens connected CPT1C-mediated GluA1 depalmitoylation and mTORC1 disinhibition via TSC2 to stress-induced depressive behavior and antidepressant response, generalizing the AMPAR mechanism to behavior.\",\n      \"evidence\": \"D1/D2-MSN-specific CPT1C knockdown, GluA1 depalmitoylation assay, chronic stress model, behavioral and synaptic plasticity recording, and TSC2/mTORC1 analysis\",\n      \"pmids\": [\"41741705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not independently replicated\", \"Mechanism of TSC2 targeting not biochemically defined\", \"Cell-type-specific circuit logic incompletely mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CPT1C's weak acyltransferase activity, palmitoyl thioesterase activity, and malonyl-CoA sensing are integrated into a single biochemical mechanism—and what structural features underlie SAC1 inhibition, protrudin binding, and substrate recognition—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CPT1C bound to malonyl-CoA, GluA1, SAC1, or protrudin\", \"Full physiological substrate repertoire of the thioesterase activity undefined\", \"Whether catalytic and sensing functions are mechanistically coupled is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 10, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 6, 21]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 9, 17]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GRIA1\", \"GRIA2\", \"ATL1\", \"ZFYVE27\", \"SACM1L\", \"ANKRD13\", \"ESRRA\", \"YY1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":11,"faith_total":11,"faith_pct":100.0}}