{"gene":"TBC1D15","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2012,"finding":"Fis1 acts as a mitochondrial recruitment factor for TBC1D15: Fis1 and TBC1D15 form a direct and stable complex (demonstrated with bacterially expressed proteins), and coexpression with Fis1 relocalized TBC1D15 from cytoplasm to mitochondria. Knockdown of TBC1D15 induced highly developed mitochondrial network structures (hyperfusion) similar to Fis1 knockdown, independently of Drp1.","method":"Co-immunoprecipitation, in vitro binding with bacterially expressed proteins, subcellular localization by fluorescence microscopy, siRNA knockdown with mitochondrial morphology readout","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct complex reconstitution with purified bacterial proteins plus reciprocal Co-IP and functional localization/knockdown phenotype in the same study","pmids":["23077178"],"is_preprint":false},{"year":2010,"finding":"TBC1D15 functions as a selective Rab7 GTPase-activating protein (GAP) in cells, reducing Rab7-GTP levels (measured by effector pulldown with RILP), fragmenting lysosomes, and conferring resistance to growth factor withdrawal-induced cell death. TBC1D15 GAP activity was selective for Rab7 and did not affect Rab4-, Rab5-, or Rab11-dependent processes.","method":"Effector pulldown assay (RILP binding to Rab7-GTP), lysosomal morphology imaging, cell survival assay, transferrin internalization/recycling assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal cellular assays establishing substrate selectivity and functional consequence of Rab7 GAP activity in single rigorous study","pmids":["20363736"],"is_preprint":false},{"year":2017,"finding":"Crystal structures of TBC1D15 GAP domain (shark and pig orthologs) resolved to 2.8 Å and 2.5 Å revealed structural conservation within the TBC1D15 family and showed variations compared to yeast Gyp1p and TBC1D1. Active-site mutagenesis demonstrated that the catalytic arginine and glutamine residues are essential for GAP activity; substitution to alanine or lysine abolished activity.","method":"X-ray crystallography, in vitro GAP activity assay, active-site mutagenesis","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro reconstitution and active-site mutagenesis in the same study","pmids":["28168758"],"is_preprint":false},{"year":2013,"finding":"TBC1D15 was identified as a Numb-associated protein by large-scale affinity purification and tandem mass spectrometry. The amino-terminal domain of TBC1D15 disengages p53 from the Numb-p53 complex, triggering p53 proteolysis and promoting stem cell self-renewal and pluripotency. TBC1D15 protein levels are reduced by autophagy-mediated degradation upon nutrient deprivation.","method":"Affinity purification and tandem mass spectrometry, co-immunoprecipitation, domain mapping, cell self-renewal and pluripotency assays, autophagy inhibitor experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — MS identification plus Co-IP and functional domain mapping in single lab study","pmids":["23468968"],"is_preprint":false},{"year":2013,"finding":"Depletion of TBC1D15 by siRNA induced RhoA activation and membrane blebbing, which was abolished by a RhoA signaling inhibitor. TBC1D15 is also required for proper accumulation of RhoA at the equatorial cortex during cytokinesis, establishing a role for TBC1D15 in regulating RhoA activity during membrane dynamics and cell division.","method":"siRNA knockdown, RhoA activation assay, membrane bleb quantification, RhoA inhibitor treatment, fluorescence microscopy of cytokinesis","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — single lab, loss-of-function with defined molecular (RhoA activation) and cellular (blebbing, cytokinesis) phenotypes","pmids":["24337944"],"is_preprint":false},{"year":2013,"finding":"The Drosophila TBC1D15 ortholog Tbc1d15-17 is required for normal presynaptic growth and postsynaptic organization at the NMJ. Loss-of-function or presynaptic knockdown increased synaptic bouton number and NMJ length. Genetic epistasis showed that presynaptic overexpression of constitutively active Rab7 phenocopied tbc1d15-17 mutants (overgrowth), while dominant-negative Rab7 had the opposite effect, placing Tbc1d15-17 upstream of Rab7 in synaptic development.","method":"Drosophila genetics (loss-of-function mutant, tissue-specific RNAi), epistasis with constitutively active and dominant-negative Rab7, NMJ morphology analysis","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in model organism with multiple alleles and orthogonal Rab7 activity manipulations","pmids":["23812537"],"is_preprint":false},{"year":2019,"finding":"Annexin A6 (AnxA6) promotes Rab7 inactivation via TBC1D15 (Rab7-GAP). AnxA6 overexpression induces late endosomal cholesterol accumulation dependent on TBC1D15-mediated Rab7 inactivation. AnxA6 depletion in NPC1 mutant cells leads to Rab7 activation, peripheral redistribution of late endosomes, and StARD3-dependent cholesterol transfer to the ER via membrane contact sites.","method":"Co-immunoprecipitation, fluorescence microscopy of late endosome localization, cholesterol accumulation assays, electron microscopy of membrane contact sites, genetic depletion experiments","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — single lab, multiple complementary methods linking AnxA6-TBC1D15-Rab7 axis to cholesterol trafficking","pmids":["31664461"],"is_preprint":false},{"year":2020,"finding":"TBC1D15 loosens abnormal mitochondria-lysosome contacts after myocardial infarction through both its Fis1-binding domain and its Rab7 GAP domain. Interference with either domain reversed TBC1D15-dependent beneficial effects on lysosomal function and mitophagy flux, establishing that both interaction surfaces are required for TBC1D15's role in mitochondria-lysosome contact regulation.","method":"Domain-specific mutant overexpression (Fis1-binding and GAP-domain mutants), transmission electron microscopy of mitochondria-lysosome contacts, live-cell time-lapse imaging, mitophagy flux assay (fluorescence and western blot), adenoviral cardiac overexpression in mice","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific mutant rescue experiments in vitro and in vivo, single lab","pmids":["33042281"],"is_preprint":false},{"year":2022,"finding":"TBC1D15 directly interacts with Drp1 through its C-terminal domain (residues 574-624), recruiting Drp1 to mitochondria-lysosome contact sites to promote asymmetrical mitochondrial fission. TBC1D15 mutants lacking this domain (Δ574-624) failed to support asymmetrical fission and mitochondrial function, and could not rescue cardiac phenotypes in TBC1D15 knockout mice after I/R injury.","method":"Co-immunoprecipitation, time-lapse confocal microscopy, domain-deletion mutant analysis, cardiac-specific knockout/knockin mouse models, adenoviral rescue with wild-type vs. mutant TBC1D15","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus domain deletion rescue in vivo with cardiac KO/KI mice, single lab","pmids":["35680100"],"is_preprint":false},{"year":2023,"finding":"Following lysosomal membrane damage, LIMP2 acts as a lysophagy receptor to recruit ATG8, which in turn recruits TBC1D15 to damaged lysosomes. TBC1D15 interacts with ATG8 proteins and provides a scaffold to assemble the autophagic lysosomal reformation (ALR) machinery including dynamin-2, kinesin-5B, and clathrin, enabling lysosomal tubulation and scission for membrane regeneration.","method":"Proximity-labeling proteomics, co-immunoprecipitation, high-resolution microscopy, genetic depletion of TBC1D15 and ALR components, lysosomal damage model (oxalate nephropathy cell culture)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — proximity proteomics combined with biochemistry and high-resolution microscopy in a rigorous study, published in high-tier journal","pmids":["37024685"],"is_preprint":false},{"year":2017,"finding":"TBC1D15 knockdown rescued nigericin-induced suppression of the STING innate immune pathway, while knockdown of Drp1 (also rescuing mitochondrial fission) did not restore STING activity. This establishes a specific, Drp1-independent role for TBC1D15 in maintaining STING pathway competency during mitochondrial fragmentation induced by inflammasome-activating signals.","method":"siRNA knockdown, STING pathway reporter assays (IFN-β, ISG56), mitochondrial morphology imaging, genetic epistasis between TBC1D15, Drp1, and NLRP3","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic epistasis with functional pathway readout in single lab; specificity confirmed by Drp1 negative control","pmids":["28729291"],"is_preprint":false},{"year":2023,"finding":"TBC1D15 interacts with DNA-PKcs at its segment 594-624. TBC1D15 promotes cytosolic retention of DNA-PKcs, contributing to DNA damage signaling; a TBC1D15 deletion mutant lacking residues 594-624 failed to elicit cytosolic DNA-PKcs accumulation or exacerbate DOX-induced DNA damage and cardiomyocyte apoptosis.","method":"Liquid chromatography-tandem mass spectrometry, co-immunoprecipitation, domain-deletion mutant analysis, cardiac-specific knockout/knockin mouse models, DNA damage assays","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP with domain mapping and in vivo rescue, single lab","pmids":["38045047"],"is_preprint":false},{"year":2018,"finding":"TBC1D15 knockout (CRISPR/Cas9) caused reduced glucose uptake, decreased total GLUT4 levels, and increased co-localization of GLUT4 with Rab7-positive late endosomes/lysosomes, demonstrating that TBC1D15-mediated Rab7-GAP activity controls GLUT4 routing through the late endosomal pathway to regulate glucose transporter surface availability.","method":"CRISPR/Cas9 knockout, 2-NBDG glucose uptake assay, GLUT4 western blot, immunofluorescence co-localization with Rab7/Lamp1","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — CRISPR KO with functional glucose uptake and localization readouts, single lab","pmids":["30316925"],"is_preprint":false},{"year":2020,"finding":"IFN-β induces expression of Mir1 microRNA, which reduces TBC1D15 levels, thereby decreasing Rab7 activity and stimulating macroautophagy. This MIR1-TBC1D15-RAB7 pathway is conserved from humans to C. elegans and represents a mechanism by which IFN-β regulates autophagic flux.","method":"miRNA overexpression, TBC1D15 knockdown, Rab7 activity measurement, autophagy flux assays, C. elegans genetic validation","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pathway validated in multiple organisms with functional autophagy readout, single lab","pmids":["31958036"],"is_preprint":false},{"year":2023,"finding":"A conserved SKY insert (S45, K46, Y47) in FIS1's first TPR repeat is required for proper TBC1D15 recruitment to mitochondria. Deletion of SKY impaired mitochondrial recruitment of both TBC1D15 and DRP1, while the SKY-to-AAA substitution enhanced TBC1D15-driven DRP1 recruitment, indicating intramolecular regulation of FIS1 activity governs TBC1D15 and DRP1 docking.","method":"Site-directed mutagenesis, co-immunoprecipitation, fluorescence microscopy of YFP-TBC1D15 localization, mitochondrial morphology analysis in HCT116 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-guided mutagenesis with functional localization and morphology readouts, single lab","pmids":["37777154"],"is_preprint":false},{"year":2024,"finding":"TBC1D15 stabilizes NOTCH1 by blocking CDK8- and CDK19-mediated phosphorylation of the NOTCH1 PEST phosphodegron, thereby preventing FBW7 E3 ligase recruitment to Thr-2512 of NOTCH1. TBC1D15 interacts with full-length NUMB and NUMB isoform 5 and relocalizes NUMB5 to mitochondria. The NOTCH1-TBC1D15-FIS1 interaction recruits mitochondria to the perinuclear region.","method":"Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation, phosphorylation assays, hepatocyte-specific triple knockout mouse model, PDX mouse model","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with phosphorylation mechanism and in vivo genetic mouse model, single lab","pmids":["38409448"],"is_preprint":false},{"year":2025,"finding":"TBC1D15 translocates to mitochondrial membranes in hepatocytes upon alcohol exposure and recruits PLIN5 through its N-terminal 10-180 aa domain. This interaction promotes mitochondria-lipid droplet contacts and facilitates PKA-induced nuclear translocation of PLIN5, upregulating PPARα, PGC1α and CPT1α to enhance fatty acid β-oxidation.","method":"Co-immunoprecipitation, domain mapping, immunofluorescence of mitochondria-LD contacts, transmission electron microscopy, PKA inhibitor experiments, hepatocyte-specific TBC1D15 overexpression mouse model","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain mapping plus pharmacological and in vivo validation, single lab","pmids":["40334909"],"is_preprint":false},{"year":2026,"finding":"TBC1D15 functions as a GAP for Arl4D (an Arf-family GTPase) in addition to Rab7: TBC1D15 interacts with Arl4D through its TBC domain and promotes GTP hydrolysis of Arl4D. TBC1D15 knockdown increases Arl4D activity and decreases Arl4D mitochondrial translocation under serum starvation, establishing TBC1D15 as a regulator of Arl4D-dependent mitochondrial homeostasis.","method":"Co-immunoprecipitation, in vitro GAP activity assay, subcellular fractionation/localization by fluorescence microscopy, TBC1D15 knockdown with Arl4D activity readout","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro GAP assay plus cellular localization and knockdown, single lab, novel substrate","pmids":["41709823"],"is_preprint":false},{"year":2024,"finding":"In vivo knockdown of murine Tbc1d15 activates autophagy, reduces α-synuclein-mediated neurotoxicity, and improves motor performance in a Parkinson's disease mouse model, corroborating that TBC1D15 inhibits autophagic flux through Rab7 regulation and that its reduction is neuroprotective.","method":"In vivo Tbc1d15 knockdown (lentiviral/AAV), autophagy flux assays, α-synuclein aggregation quantification, motor performance behavioral assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2-3 / Weak — preprint, single lab, functional in vivo data but no direct molecular mechanism beyond Rab7/autophagy axis already established","pmids":[],"is_preprint":true}],"current_model":"TBC1D15 is a Rab7 GTPase-activating protein (GAP) — and also a GAP for Arl4D — that localizes to mitochondria via direct binding to the outer membrane protein FIS1; at mitochondria it recruits DRP1 through its C-terminal domain (574-624) to promote asymmetrical mitochondrial fission, regulates the duration of mitochondria-lysosome membrane contacts through its Fis1-binding and Rab7-GAP domains, scaffolds the autophagic lysosomal reformation machinery (via ATG8 interaction) to regenerate damaged lysosomal membranes, controls late endosomal Rab7-GTP levels to regulate lysosomal morphology and GLUT4 trafficking, destabilizes the Numb-p53 complex (through its N-terminal domain) to promote stem cell self-renewal, stabilizes NOTCH1 by blocking CDK8-mediated phosphodegron phosphorylation, binds DNA-PKcs (at residues 594-624) to promote its cytosolic retention, and interacts with PLIN5 (via residues 10-180) to promote mitochondria-lipid droplet contacts and fatty acid oxidation."},"narrative":{"mechanistic_narrative":"TBC1D15 is a Rab7-selective GTPase-activating protein (GAP) that couples late-endosomal/lysosomal Rab7-GTP regulation to mitochondrial dynamics, membrane-contact-site biology, and autophagic flux [PMID:20363736]. Its GAP activity is selective for Rab7 over Rab4, Rab5, and Rab11, lowers cellular Rab7-GTP, fragments lysosomes, and confers resistance to growth-factor-withdrawal death [PMID:20363736]; crystal structures of the GAP domain confirm a conserved TBC fold whose catalytic arginine and glutamine residues are essential for activity [PMID:28168758]. TBC1D15 is recruited to the mitochondrial outer membrane through a direct, reconstituted complex with FIS1, and loss of either protein produces a hyperfused mitochondrial network independently of DRP1 [PMID:23077178, PMID:37777154]. At mitochondria it functions through two interaction surfaces — its FIS1-binding domain and its Rab7-GAP domain — to govern mitochondria-lysosome contacts [PMID:33042281], and through its C-terminal domain (574-624) it recruits DRP1 to these contacts to drive asymmetrical mitochondrial fission [PMID:35680100]. By controlling Rab7 activity TBC1D15 sets a brake on autophagic flux: its depletion or downregulation (via the IFN-β-induced miR-1 axis) raises autophagy [PMID:31958036], and following lysosomal membrane damage ATG8 recruits TBC1D15 to scaffold the autophagic lysosomal reformation machinery (dynamin-2, kinesin-5B, clathrin) for membrane regeneration [PMID:37024685]. The same Rab7-GAP activity routes cargo through the late-endosomal system, controlling GLUT4 surface availability and glucose uptake [PMID:30316925] and, with Annexin A6, late-endosomal cholesterol handling [PMID:31664461]. Beyond GTPase regulation, TBC1D15 destabilizes the Numb-p53 complex via its N-terminal domain to promote stem-cell self-renewal [PMID:23468968], stabilizes NOTCH1 by blocking CDK8/CDK19 phosphodegron phosphorylation [PMID:38409448], and links mitochondria to lipid droplets through a PLIN5 interaction that enhances fatty-acid β-oxidation [PMID:40334909].","teleology":[{"year":2010,"claim":"Established the core biochemical identity of TBC1D15 as a substrate-selective Rab7 GAP with a defined cellular consequence, answering what GTPase it regulates.","evidence":"RILP effector pulldown of Rab7-GTP, lysosomal morphology imaging, cell survival assays in cells","pmids":["20363736"],"confidence":"High","gaps":["Did not resolve how TBC1D15 is localized to its site of action","Substrate range beyond Rab4/5/7/11 not exhaustively tested"]},{"year":2012,"claim":"Resolved how TBC1D15 reaches mitochondria, showing FIS1 is a direct recruitment factor and that the pair restrains mitochondrial fusion independently of Drp1.","evidence":"In vitro binding with bacterially expressed proteins, reciprocal Co-IP, localization microscopy, and siRNA morphology readout","pmids":["23077178"],"confidence":"High","gaps":["How FIS1 binding relates to Rab7-GAP activity unresolved","Did not define the mitochondrial fission machinery linkage"]},{"year":2013,"claim":"Extended TBC1D15 function beyond GTPase regulation into transcription/stemness control by identifying a Numb-p53-destabilizing activity.","evidence":"Affinity purification/MS, Co-IP, domain mapping, self-renewal and pluripotency assays","pmids":["23468968"],"confidence":"Medium","gaps":["Mechanism of p53 disengagement from Numb not structurally defined","Relationship to GAP activity unclear"]},{"year":2013,"claim":"Placed TBC1D15 upstream of Rab7 in a developmental context, using Drosophila epistasis to confirm directionality of the GAP-Rab7 relationship in vivo.","evidence":"Drosophila loss-of-function and RNAi with constitutively active/dominant-negative Rab7 epistasis at the NMJ","pmids":["23812537"],"confidence":"Medium","gaps":["Mammalian synaptic relevance not tested","Effectors downstream of Rab7 not identified"]},{"year":2013,"claim":"Linked TBC1D15 to RhoA-dependent membrane and cytokinetic dynamics, broadening its role in cell division.","evidence":"siRNA knockdown, RhoA activation assay, blebbing quantification, RhoA inhibitor, cytokinesis imaging","pmids":["24337944"],"confidence":"Medium","gaps":["Direct molecular link between TBC1D15 and RhoA regulation not established","Whether this requires Rab7-GAP activity unknown"]},{"year":2017,"claim":"Provided the structural and catalytic basis of GAP activity, defining the essential active-site residues.","evidence":"X-ray crystallography of shark and pig GAP domains, in vitro GAP assays, active-site mutagenesis","pmids":["28168758"],"confidence":"High","gaps":["No structure of full-length protein or substrate complex","Determinants of Arl4D vs Rab7 selectivity not defined"]},{"year":2017,"claim":"Distinguished TBC1D15's role in innate immunity from its fission function, showing a Drp1-independent requirement for STING competency.","evidence":"siRNA knockdown, STING reporter assays, genetic epistasis with Drp1 and NLRP3","pmids":["28729291"],"confidence":"Medium","gaps":["Molecular mechanism connecting TBC1D15 to STING not defined","Whether Rab7-GAP activity is involved unknown"]},{"year":2018,"claim":"Connected Rab7-GAP activity to physiological cargo handling, showing TBC1D15 controls GLUT4 routing and glucose uptake.","evidence":"CRISPR/Cas9 knockout, glucose uptake assay, GLUT4 western blot, Rab7/Lamp1 co-localization","pmids":["30316925"],"confidence":"Medium","gaps":["Whether GLUT4 effect is direct or systemic not resolved","In vivo metabolic relevance untested"]},{"year":2019,"claim":"Embedded TBC1D15 in a regulatory axis controlling late-endosomal cholesterol transfer via Annexin A6 and membrane contact sites.","evidence":"Co-IP, late-endosome localization microscopy, cholesterol assays, EM of contact sites, depletion in NPC1 mutant cells","pmids":["31664461"],"confidence":"Medium","gaps":["Whether AnxA6 directly modulates TBC1D15 catalysis unknown","Stoichiometry of the AnxA6-TBC1D15 complex undefined"]},{"year":2020,"claim":"Defined two distinct interaction surfaces (FIS1-binding and GAP) as jointly required for tuning mitochondria-lysosome contact duration in cardiac injury.","evidence":"Domain-specific mutant rescue, TEM of contacts, live-cell imaging, mitophagy flux, adenoviral cardiac overexpression in mice","pmids":["33042281"],"confidence":"Medium","gaps":["How the two domains are coordinated mechanistically unresolved","Single disease model"]},{"year":2020,"claim":"Identified a conserved miR-1-TBC1D15-Rab7 regulatory pathway by which IFN-β raises autophagic flux.","evidence":"miRNA overexpression, knockdown, Rab7 activity measurement, autophagy flux assays, C. elegans validation","pmids":["31958036"],"confidence":"Medium","gaps":["Direct miR-1 targeting of TBC1D15 transcript not fully mapped","Physiological IFN-β contexts limited"]},{"year":2022,"claim":"Pinpointed the C-terminal 574-624 region as the DRP1-recruiting module that enables asymmetrical mitochondrial fission at contact sites.","evidence":"Co-IP, time-lapse confocal microscopy, Δ574-624 deletion, cardiac KO/KI mice, adenoviral rescue","pmids":["35680100"],"confidence":"Medium","gaps":["Structural basis of TBC1D15-DRP1 binding not solved","How fission asymmetry is spatially determined unclear"]},{"year":2023,"claim":"Revealed a scaffolding role downstream of lysosomal damage, where ATG8 recruits TBC1D15 to assemble the autophagic lysosomal reformation machinery for membrane regeneration.","evidence":"Proximity-labeling proteomics, Co-IP, high-resolution microscopy, depletion of TBC1D15 and ALR components, lysosomal damage model","pmids":["37024685"],"confidence":"High","gaps":["Whether GAP catalysis is required for ALR scaffolding unresolved","Interaction interfaces with ATG8 and ALR components not mapped"]},{"year":2023,"claim":"Mapped a FIS1 SKY insert as the determinant of TBC1D15 and DRP1 mitochondrial docking, linking FIS1 intramolecular regulation to fission machinery recruitment.","evidence":"Site-directed mutagenesis, Co-IP, YFP-TBC1D15 localization microscopy, morphology analysis in HCT116 cells","pmids":["37777154"],"confidence":"Medium","gaps":["Structural mechanism of SKY-mediated regulation undefined","How SKY state is physiologically controlled unknown"]},{"year":2023,"claim":"Identified a non-GAP nuclear/DNA-damage role, with a 594-624 segment binding DNA-PKcs to promote its cytosolic retention.","evidence":"LC-MS/MS, Co-IP, Δ594-624 deletion, cardiac KO/KI mice, DNA damage assays","pmids":["38045047"],"confidence":"Medium","gaps":["Overlap of the DNA-PKcs and DRP1 binding regions not reconciled","Mechanism of cytosolic retention undefined"]},{"year":2024,"claim":"Connected TBC1D15 to NOTCH1 stability and NUMB handling, blocking CDK8/CDK19 phosphodegron phosphorylation to prevent FBW7-mediated degradation.","evidence":"ChIP-seq, Co-IP, phosphorylation assays, hepatocyte triple-KO and PDX mouse models","pmids":["38409448"],"confidence":"Medium","gaps":["How TBC1D15 physically shields the phosphodegron unknown","Relationship to mitochondrial functions unclear"]},{"year":2025,"claim":"Defined a PLIN5-dependent mechanism by which TBC1D15 promotes mitochondria-lipid droplet contacts and fatty-acid β-oxidation.","evidence":"Co-IP, domain mapping (10-180 aa), contact-site immunofluorescence, TEM, PKA inhibitor, hepatocyte overexpression mouse model","pmids":["40334909"],"confidence":"Medium","gaps":["Whether this is GAP-independent not formally tested","Trigger for TBC1D15 mitochondrial translocation upon alcohol exposure undefined"]},{"year":2026,"claim":"Expanded TBC1D15's substrate range, showing it is also a GAP for the Arf-family GTPase Arl4D acting through its TBC domain.","evidence":"Co-IP, in vitro GAP assay, localization microscopy, knockdown with Arl4D activity readout","pmids":["41709823"],"confidence":"Medium","gaps":["Determinants of dual Rab7/Arl4D selectivity unresolved","Physiological balance between the two substrates unknown"]},{"year":null,"claim":"It remains unresolved how TBC1D15's GAP catalysis, its FIS1/DRP1 scaffolding at mitochondria, and its GAP-independent protein-stability roles (Numb-p53, NOTCH1, DNA-PKcs) are integrated within a single protein and which functions are coupled versus separable.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length structure showing how distinct functional modules coexist","Whether GAP activity is required for scaffolding/protein-stability roles untested","Tissue- and stimulus-specific selection among functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,17,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,9,16]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,8,14,16]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1,9,7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,11]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,8,7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,12]}],"complexes":[],"partners":["FIS1","RAB7","DRP1","ATG8","NUMB","NOTCH1","PLIN5","ARL4D"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TC07","full_name":"TBC1 domain family member 15","aliases":["GTPase-activating protein RAB7","GAP for RAB7","Rab7-GAP"],"length_aa":691,"mass_kda":79.5,"function":"Acts as a GTPase activating protein for RAB7A. Does not act on RAB4, RAB5 or RAB6 (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8TC07/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TBC1D15","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TBC1D15","total_profiled":1310},"omim":[{"mim_id":"620377","title":"ARMADILLO REPEAT-CONTAINING PROTEIN 12; ARMC12","url":"https://www.omim.org/entry/620377"},{"mim_id":"614166","title":"MYOPIA 20, AUTOSOMAL DOMINANT; MYP20","url":"https://www.omim.org/entry/614166"},{"mim_id":"612662","title":"TBC1 DOMAIN FAMILY, MEMBER 15; TBC1D15","url":"https://www.omim.org/entry/612662"},{"mim_id":"602298","title":"RAS-ASSOCIATED PROTEIN RAB7A; RAB7A","url":"https://www.omim.org/entry/602298"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TBC1D15"},"hgnc":{"alias_symbol":["FLJ12085","DKFZp761D0223"],"prev_symbol":[]},"alphafold":{"accession":"Q8TC07","domains":[{"cath_id":"2.30.29.230","chopping":"11-56_126-196","consensus_level":"high","plddt":79.738,"start":11,"end":196},{"cath_id":"1.10.472.80","chopping":"276-328_488-632","consensus_level":"medium","plddt":86.5547,"start":276,"end":632},{"cath_id":"1.10.8.270","chopping":"348-484","consensus_level":"high","plddt":95.5133,"start":348,"end":484}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TC07","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TC07-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TC07-F1-predicted_aligned_error_v6.png","plddt_mean":70.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TBC1D15","jax_strain_url":"https://www.jax.org/strain/search?query=TBC1D15"},"sequence":{"accession":"Q8TC07","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TC07.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TC07/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TC07"}},"corpus_meta":[{"pmid":"23077178","id":"PMC_23077178","title":"Fis1 acts as a mitochondrial recruitment factor for TBC1D15 that is involved in regulation of mitochondrial morphology.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23077178","citation_count":124,"is_preprint":false},{"pmid":"33042281","id":"PMC_33042281","title":"TBC1D15/RAB7-regulated mitochondria-lysosome interaction confers cardioprotection against acute myocardial infarction-induced cardiac injury.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33042281","citation_count":107,"is_preprint":false},{"pmid":"20363736","id":"PMC_20363736","title":"Differential effects of TBC1D15 and mammalian Vps39 on Rab7 activation state, lysosomal morphology, and growth factor dependence.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20363736","citation_count":102,"is_preprint":false},{"pmid":"37024685","id":"PMC_37024685","title":"A lysosome membrane regeneration pathway depends on TBC1D15 and autophagic lysosomal reformation proteins.","date":"2023","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37024685","citation_count":70,"is_preprint":false},{"pmid":"31664461","id":"PMC_31664461","title":"Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/31664461","citation_count":60,"is_preprint":false},{"pmid":"35680100","id":"PMC_35680100","title":"TBC1D15-Drp1 interaction-mediated mitochondrial homeostasis confers cardioprotection against myocardial ischemia/reperfusion injury.","date":"2022","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/35680100","citation_count":57,"is_preprint":false},{"pmid":"28729291","id":"PMC_28729291","title":"Stimulator of IFN genes-mediated DNA-sensing pathway is suppressed by NLRP3 agonists and regulated by mitofusin 1 and TBC1D15, mitochondrial dynamics mediators.","date":"2017","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28729291","citation_count":25,"is_preprint":false},{"pmid":"23468968","id":"PMC_23468968","title":"The TBC1D15 oncoprotein controls stem cell self-renewal through destabilization of the Numb-p53 complex.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23468968","citation_count":22,"is_preprint":false},{"pmid":"38045047","id":"PMC_38045047","title":"TBC1D15 deficiency protects against doxorubicin cardiotoxicity via inhibiting DNA-PKcs cytosolic retention and DNA damage.","date":"2023","source":"Acta pharmaceutica Sinica. 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to reprogram tumor-initiating cells.","date":"2024","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38409448","citation_count":7,"is_preprint":false},{"pmid":"37777154","id":"PMC_37777154","title":"A conserved, noncanonical insert in FIS1 mediates TBC1D15 and DRP1 recruitment for mitochondrial fission.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37777154","citation_count":7,"is_preprint":false},{"pmid":"23812537","id":"PMC_23812537","title":"Tbc1d15-17 regulates synaptic development at the Drosophila neuromuscular junction.","date":"2013","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/23812537","citation_count":7,"is_preprint":false},{"pmid":"39740704","id":"PMC_39740704","title":"The role of TBC1D15 in sepsis-induced acute lung injury: Regulation of mitochondrial homeostasis and mitophagy.","date":"2024","source":"International journal of biological 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factor for TBC1D15: Fis1 and TBC1D15 form a direct and stable complex (demonstrated with bacterially expressed proteins), and coexpression with Fis1 relocalized TBC1D15 from cytoplasm to mitochondria. Knockdown of TBC1D15 induced highly developed mitochondrial network structures (hyperfusion) similar to Fis1 knockdown, independently of Drp1.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding with bacterially expressed proteins, subcellular localization by fluorescence microscopy, siRNA knockdown with mitochondrial morphology readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct complex reconstitution with purified bacterial proteins plus reciprocal Co-IP and functional localization/knockdown phenotype in the same study\",\n      \"pmids\": [\"23077178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TBC1D15 functions as a selective Rab7 GTPase-activating protein (GAP) in cells, reducing Rab7-GTP levels (measured by effector pulldown with RILP), fragmenting lysosomes, and conferring resistance to growth factor withdrawal-induced cell death. TBC1D15 GAP activity was selective for Rab7 and did not affect Rab4-, Rab5-, or Rab11-dependent processes.\",\n      \"method\": \"Effector pulldown assay (RILP binding to Rab7-GTP), lysosomal morphology imaging, cell survival assay, transferrin internalization/recycling assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal cellular assays establishing substrate selectivity and functional consequence of Rab7 GAP activity in single rigorous study\",\n      \"pmids\": [\"20363736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of TBC1D15 GAP domain (shark and pig orthologs) resolved to 2.8 Å and 2.5 Å revealed structural conservation within the TBC1D15 family and showed variations compared to yeast Gyp1p and TBC1D1. Active-site mutagenesis demonstrated that the catalytic arginine and glutamine residues are essential for GAP activity; substitution to alanine or lysine abolished activity.\",\n      \"method\": \"X-ray crystallography, in vitro GAP activity assay, active-site mutagenesis\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro reconstitution and active-site mutagenesis in the same study\",\n      \"pmids\": [\"28168758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TBC1D15 was identified as a Numb-associated protein by large-scale affinity purification and tandem mass spectrometry. The amino-terminal domain of TBC1D15 disengages p53 from the Numb-p53 complex, triggering p53 proteolysis and promoting stem cell self-renewal and pluripotency. TBC1D15 protein levels are reduced by autophagy-mediated degradation upon nutrient deprivation.\",\n      \"method\": \"Affinity purification and tandem mass spectrometry, co-immunoprecipitation, domain mapping, cell self-renewal and pluripotency assays, autophagy inhibitor experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — MS identification plus Co-IP and functional domain mapping in single lab study\",\n      \"pmids\": [\"23468968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Depletion of TBC1D15 by siRNA induced RhoA activation and membrane blebbing, which was abolished by a RhoA signaling inhibitor. TBC1D15 is also required for proper accumulation of RhoA at the equatorial cortex during cytokinesis, establishing a role for TBC1D15 in regulating RhoA activity during membrane dynamics and cell division.\",\n      \"method\": \"siRNA knockdown, RhoA activation assay, membrane bleb quantification, RhoA inhibitor treatment, fluorescence microscopy of cytokinesis\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — single lab, loss-of-function with defined molecular (RhoA activation) and cellular (blebbing, cytokinesis) phenotypes\",\n      \"pmids\": [\"24337944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The Drosophila TBC1D15 ortholog Tbc1d15-17 is required for normal presynaptic growth and postsynaptic organization at the NMJ. Loss-of-function or presynaptic knockdown increased synaptic bouton number and NMJ length. Genetic epistasis showed that presynaptic overexpression of constitutively active Rab7 phenocopied tbc1d15-17 mutants (overgrowth), while dominant-negative Rab7 had the opposite effect, placing Tbc1d15-17 upstream of Rab7 in synaptic development.\",\n      \"method\": \"Drosophila genetics (loss-of-function mutant, tissue-specific RNAi), epistasis with constitutively active and dominant-negative Rab7, NMJ morphology analysis\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in model organism with multiple alleles and orthogonal Rab7 activity manipulations\",\n      \"pmids\": [\"23812537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Annexin A6 (AnxA6) promotes Rab7 inactivation via TBC1D15 (Rab7-GAP). AnxA6 overexpression induces late endosomal cholesterol accumulation dependent on TBC1D15-mediated Rab7 inactivation. AnxA6 depletion in NPC1 mutant cells leads to Rab7 activation, peripheral redistribution of late endosomes, and StARD3-dependent cholesterol transfer to the ER via membrane contact sites.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy of late endosome localization, cholesterol accumulation assays, electron microscopy of membrane contact sites, genetic depletion experiments\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — single lab, multiple complementary methods linking AnxA6-TBC1D15-Rab7 axis to cholesterol trafficking\",\n      \"pmids\": [\"31664461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TBC1D15 loosens abnormal mitochondria-lysosome contacts after myocardial infarction through both its Fis1-binding domain and its Rab7 GAP domain. Interference with either domain reversed TBC1D15-dependent beneficial effects on lysosomal function and mitophagy flux, establishing that both interaction surfaces are required for TBC1D15's role in mitochondria-lysosome contact regulation.\",\n      \"method\": \"Domain-specific mutant overexpression (Fis1-binding and GAP-domain mutants), transmission electron microscopy of mitochondria-lysosome contacts, live-cell time-lapse imaging, mitophagy flux assay (fluorescence and western blot), adenoviral cardiac overexpression in mice\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific mutant rescue experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"33042281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TBC1D15 directly interacts with Drp1 through its C-terminal domain (residues 574-624), recruiting Drp1 to mitochondria-lysosome contact sites to promote asymmetrical mitochondrial fission. TBC1D15 mutants lacking this domain (Δ574-624) failed to support asymmetrical fission and mitochondrial function, and could not rescue cardiac phenotypes in TBC1D15 knockout mice after I/R injury.\",\n      \"method\": \"Co-immunoprecipitation, time-lapse confocal microscopy, domain-deletion mutant analysis, cardiac-specific knockout/knockin mouse models, adenoviral rescue with wild-type vs. mutant TBC1D15\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus domain deletion rescue in vivo with cardiac KO/KI mice, single lab\",\n      \"pmids\": [\"35680100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Following lysosomal membrane damage, LIMP2 acts as a lysophagy receptor to recruit ATG8, which in turn recruits TBC1D15 to damaged lysosomes. TBC1D15 interacts with ATG8 proteins and provides a scaffold to assemble the autophagic lysosomal reformation (ALR) machinery including dynamin-2, kinesin-5B, and clathrin, enabling lysosomal tubulation and scission for membrane regeneration.\",\n      \"method\": \"Proximity-labeling proteomics, co-immunoprecipitation, high-resolution microscopy, genetic depletion of TBC1D15 and ALR components, lysosomal damage model (oxalate nephropathy cell culture)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — proximity proteomics combined with biochemistry and high-resolution microscopy in a rigorous study, published in high-tier journal\",\n      \"pmids\": [\"37024685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TBC1D15 knockdown rescued nigericin-induced suppression of the STING innate immune pathway, while knockdown of Drp1 (also rescuing mitochondrial fission) did not restore STING activity. This establishes a specific, Drp1-independent role for TBC1D15 in maintaining STING pathway competency during mitochondrial fragmentation induced by inflammasome-activating signals.\",\n      \"method\": \"siRNA knockdown, STING pathway reporter assays (IFN-β, ISG56), mitochondrial morphology imaging, genetic epistasis between TBC1D15, Drp1, and NLRP3\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic epistasis with functional pathway readout in single lab; specificity confirmed by Drp1 negative control\",\n      \"pmids\": [\"28729291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TBC1D15 interacts with DNA-PKcs at its segment 594-624. TBC1D15 promotes cytosolic retention of DNA-PKcs, contributing to DNA damage signaling; a TBC1D15 deletion mutant lacking residues 594-624 failed to elicit cytosolic DNA-PKcs accumulation or exacerbate DOX-induced DNA damage and cardiomyocyte apoptosis.\",\n      \"method\": \"Liquid chromatography-tandem mass spectrometry, co-immunoprecipitation, domain-deletion mutant analysis, cardiac-specific knockout/knockin mouse models, DNA damage assays\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP with domain mapping and in vivo rescue, single lab\",\n      \"pmids\": [\"38045047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TBC1D15 knockout (CRISPR/Cas9) caused reduced glucose uptake, decreased total GLUT4 levels, and increased co-localization of GLUT4 with Rab7-positive late endosomes/lysosomes, demonstrating that TBC1D15-mediated Rab7-GAP activity controls GLUT4 routing through the late endosomal pathway to regulate glucose transporter surface availability.\",\n      \"method\": \"CRISPR/Cas9 knockout, 2-NBDG glucose uptake assay, GLUT4 western blot, immunofluorescence co-localization with Rab7/Lamp1\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — CRISPR KO with functional glucose uptake and localization readouts, single lab\",\n      \"pmids\": [\"30316925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IFN-β induces expression of Mir1 microRNA, which reduces TBC1D15 levels, thereby decreasing Rab7 activity and stimulating macroautophagy. This MIR1-TBC1D15-RAB7 pathway is conserved from humans to C. elegans and represents a mechanism by which IFN-β regulates autophagic flux.\",\n      \"method\": \"miRNA overexpression, TBC1D15 knockdown, Rab7 activity measurement, autophagy flux assays, C. elegans genetic validation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pathway validated in multiple organisms with functional autophagy readout, single lab\",\n      \"pmids\": [\"31958036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A conserved SKY insert (S45, K46, Y47) in FIS1's first TPR repeat is required for proper TBC1D15 recruitment to mitochondria. Deletion of SKY impaired mitochondrial recruitment of both TBC1D15 and DRP1, while the SKY-to-AAA substitution enhanced TBC1D15-driven DRP1 recruitment, indicating intramolecular regulation of FIS1 activity governs TBC1D15 and DRP1 docking.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation, fluorescence microscopy of YFP-TBC1D15 localization, mitochondrial morphology analysis in HCT116 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-guided mutagenesis with functional localization and morphology readouts, single lab\",\n      \"pmids\": [\"37777154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TBC1D15 stabilizes NOTCH1 by blocking CDK8- and CDK19-mediated phosphorylation of the NOTCH1 PEST phosphodegron, thereby preventing FBW7 E3 ligase recruitment to Thr-2512 of NOTCH1. TBC1D15 interacts with full-length NUMB and NUMB isoform 5 and relocalizes NUMB5 to mitochondria. The NOTCH1-TBC1D15-FIS1 interaction recruits mitochondria to the perinuclear region.\",\n      \"method\": \"Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation, phosphorylation assays, hepatocyte-specific triple knockout mouse model, PDX mouse model\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with phosphorylation mechanism and in vivo genetic mouse model, single lab\",\n      \"pmids\": [\"38409448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TBC1D15 translocates to mitochondrial membranes in hepatocytes upon alcohol exposure and recruits PLIN5 through its N-terminal 10-180 aa domain. This interaction promotes mitochondria-lipid droplet contacts and facilitates PKA-induced nuclear translocation of PLIN5, upregulating PPARα, PGC1α and CPT1α to enhance fatty acid β-oxidation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, immunofluorescence of mitochondria-LD contacts, transmission electron microscopy, PKA inhibitor experiments, hepatocyte-specific TBC1D15 overexpression mouse model\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain mapping plus pharmacological and in vivo validation, single lab\",\n      \"pmids\": [\"40334909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TBC1D15 functions as a GAP for Arl4D (an Arf-family GTPase) in addition to Rab7: TBC1D15 interacts with Arl4D through its TBC domain and promotes GTP hydrolysis of Arl4D. TBC1D15 knockdown increases Arl4D activity and decreases Arl4D mitochondrial translocation under serum starvation, establishing TBC1D15 as a regulator of Arl4D-dependent mitochondrial homeostasis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro GAP activity assay, subcellular fractionation/localization by fluorescence microscopy, TBC1D15 knockdown with Arl4D activity readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro GAP assay plus cellular localization and knockdown, single lab, novel substrate\",\n      \"pmids\": [\"41709823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In vivo knockdown of murine Tbc1d15 activates autophagy, reduces α-synuclein-mediated neurotoxicity, and improves motor performance in a Parkinson's disease mouse model, corroborating that TBC1D15 inhibits autophagic flux through Rab7 regulation and that its reduction is neuroprotective.\",\n      \"method\": \"In vivo Tbc1d15 knockdown (lentiviral/AAV), autophagy flux assays, α-synuclein aggregation quantification, motor performance behavioral assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — preprint, single lab, functional in vivo data but no direct molecular mechanism beyond Rab7/autophagy axis already established\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TBC1D15 is a Rab7 GTPase-activating protein (GAP) — and also a GAP for Arl4D — that localizes to mitochondria via direct binding to the outer membrane protein FIS1; at mitochondria it recruits DRP1 through its C-terminal domain (574-624) to promote asymmetrical mitochondrial fission, regulates the duration of mitochondria-lysosome membrane contacts through its Fis1-binding and Rab7-GAP domains, scaffolds the autophagic lysosomal reformation machinery (via ATG8 interaction) to regenerate damaged lysosomal membranes, controls late endosomal Rab7-GTP levels to regulate lysosomal morphology and GLUT4 trafficking, destabilizes the Numb-p53 complex (through its N-terminal domain) to promote stem cell self-renewal, stabilizes NOTCH1 by blocking CDK8-mediated phosphodegron phosphorylation, binds DNA-PKcs (at residues 594-624) to promote its cytosolic retention, and interacts with PLIN5 (via residues 10-180) to promote mitochondria-lipid droplet contacts and fatty acid oxidation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TBC1D15 is a Rab7-selective GTPase-activating protein (GAP) that couples late-endosomal/lysosomal Rab7-GTP regulation to mitochondrial dynamics, membrane-contact-site biology, and autophagic flux [#1]. Its GAP activity is selective for Rab7 over Rab4, Rab5, and Rab11, lowers cellular Rab7-GTP, fragments lysosomes, and confers resistance to growth-factor-withdrawal death [#1]; crystal structures of the GAP domain confirm a conserved TBC fold whose catalytic arginine and glutamine residues are essential for activity [#2]. TBC1D15 is recruited to the mitochondrial outer membrane through a direct, reconstituted complex with FIS1, and loss of either protein produces a hyperfused mitochondrial network independently of DRP1 [#0, #14]. At mitochondria it functions through two interaction surfaces — its FIS1-binding domain and its Rab7-GAP domain — to govern mitochondria-lysosome contacts [#7], and through its C-terminal domain (574-624) it recruits DRP1 to these contacts to drive asymmetrical mitochondrial fission [#8]. By controlling Rab7 activity TBC1D15 sets a brake on autophagic flux: its depletion or downregulation (via the IFN-\\u03b2-induced miR-1 axis) raises autophagy [#13], and following lysosomal membrane damage ATG8 recruits TBC1D15 to scaffold the autophagic lysosomal reformation machinery (dynamin-2, kinesin-5B, clathrin) for membrane regeneration [#9]. The same Rab7-GAP activity routes cargo through the late-endosomal system, controlling GLUT4 surface availability and glucose uptake [#12] and, with Annexin A6, late-endosomal cholesterol handling [#6]. Beyond GTPase regulation, TBC1D15 destabilizes the Numb-p53 complex via its N-terminal domain to promote stem-cell self-renewal [#3], stabilizes NOTCH1 by blocking CDK8/CDK19 phosphodegron phosphorylation [#15], and links mitochondria to lipid droplets through a PLIN5 interaction that enhances fatty-acid \\u03b2-oxidation [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the core biochemical identity of TBC1D15 as a substrate-selective Rab7 GAP with a defined cellular consequence, answering what GTPase it regulates.\",\n      \"evidence\": \"RILP effector pulldown of Rab7-GTP, lysosomal morphology imaging, cell survival assays in cells\",\n      \"pmids\": [\"20363736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how TBC1D15 is localized to its site of action\", \"Substrate range beyond Rab4/5/7/11 not exhaustively tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how TBC1D15 reaches mitochondria, showing FIS1 is a direct recruitment factor and that the pair restrains mitochondrial fusion independently of Drp1.\",\n      \"evidence\": \"In vitro binding with bacterially expressed proteins, reciprocal Co-IP, localization microscopy, and siRNA morphology readout\",\n      \"pmids\": [\"23077178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FIS1 binding relates to Rab7-GAP activity unresolved\", \"Did not define the mitochondrial fission machinery linkage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended TBC1D15 function beyond GTPase regulation into transcription/stemness control by identifying a Numb-p53-destabilizing activity.\",\n      \"evidence\": \"Affinity purification/MS, Co-IP, domain mapping, self-renewal and pluripotency assays\",\n      \"pmids\": [\"23468968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of p53 disengagement from Numb not structurally defined\", \"Relationship to GAP activity unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed TBC1D15 upstream of Rab7 in a developmental context, using Drosophila epistasis to confirm directionality of the GAP-Rab7 relationship in vivo.\",\n      \"evidence\": \"Drosophila loss-of-function and RNAi with constitutively active/dominant-negative Rab7 epistasis at the NMJ\",\n      \"pmids\": [\"23812537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian synaptic relevance not tested\", \"Effectors downstream of Rab7 not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked TBC1D15 to RhoA-dependent membrane and cytokinetic dynamics, broadening its role in cell division.\",\n      \"evidence\": \"siRNA knockdown, RhoA activation assay, blebbing quantification, RhoA inhibitor, cytokinesis imaging\",\n      \"pmids\": [\"24337944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between TBC1D15 and RhoA regulation not established\", \"Whether this requires Rab7-GAP activity unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the structural and catalytic basis of GAP activity, defining the essential active-site residues.\",\n      \"evidence\": \"X-ray crystallography of shark and pig GAP domains, in vitro GAP assays, active-site mutagenesis\",\n      \"pmids\": [\"28168758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of full-length protein or substrate complex\", \"Determinants of Arl4D vs Rab7 selectivity not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished TBC1D15's role in innate immunity from its fission function, showing a Drp1-independent requirement for STING competency.\",\n      \"evidence\": \"siRNA knockdown, STING reporter assays, genetic epistasis with Drp1 and NLRP3\",\n      \"pmids\": [\"28729291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting TBC1D15 to STING not defined\", \"Whether Rab7-GAP activity is involved unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected Rab7-GAP activity to physiological cargo handling, showing TBC1D15 controls GLUT4 routing and glucose uptake.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, glucose uptake assay, GLUT4 western blot, Rab7/Lamp1 co-localization\",\n      \"pmids\": [\"30316925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GLUT4 effect is direct or systemic not resolved\", \"In vivo metabolic relevance untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Embedded TBC1D15 in a regulatory axis controlling late-endosomal cholesterol transfer via Annexin A6 and membrane contact sites.\",\n      \"evidence\": \"Co-IP, late-endosome localization microscopy, cholesterol assays, EM of contact sites, depletion in NPC1 mutant cells\",\n      \"pmids\": [\"31664461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AnxA6 directly modulates TBC1D15 catalysis unknown\", \"Stoichiometry of the AnxA6-TBC1D15 complex undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined two distinct interaction surfaces (FIS1-binding and GAP) as jointly required for tuning mitochondria-lysosome contact duration in cardiac injury.\",\n      \"evidence\": \"Domain-specific mutant rescue, TEM of contacts, live-cell imaging, mitophagy flux, adenoviral cardiac overexpression in mice\",\n      \"pmids\": [\"33042281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the two domains are coordinated mechanistically unresolved\", \"Single disease model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a conserved miR-1-TBC1D15-Rab7 regulatory pathway by which IFN-\\u03b2 raises autophagic flux.\",\n      \"evidence\": \"miRNA overexpression, knockdown, Rab7 activity measurement, autophagy flux assays, C. elegans validation\",\n      \"pmids\": [\"31958036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miR-1 targeting of TBC1D15 transcript not fully mapped\", \"Physiological IFN-\\u03b2 contexts limited\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pinpointed the C-terminal 574-624 region as the DRP1-recruiting module that enables asymmetrical mitochondrial fission at contact sites.\",\n      \"evidence\": \"Co-IP, time-lapse confocal microscopy, \\u0394574-624 deletion, cardiac KO/KI mice, adenoviral rescue\",\n      \"pmids\": [\"35680100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of TBC1D15-DRP1 binding not solved\", \"How fission asymmetry is spatially determined unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a scaffolding role downstream of lysosomal damage, where ATG8 recruits TBC1D15 to assemble the autophagic lysosomal reformation machinery for membrane regeneration.\",\n      \"evidence\": \"Proximity-labeling proteomics, Co-IP, high-resolution microscopy, depletion of TBC1D15 and ALR components, lysosomal damage model\",\n      \"pmids\": [\"37024685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GAP catalysis is required for ALR scaffolding unresolved\", \"Interaction interfaces with ATG8 and ALR components not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped a FIS1 SKY insert as the determinant of TBC1D15 and DRP1 mitochondrial docking, linking FIS1 intramolecular regulation to fission machinery recruitment.\",\n      \"evidence\": \"Site-directed mutagenesis, Co-IP, YFP-TBC1D15 localization microscopy, morphology analysis in HCT116 cells\",\n      \"pmids\": [\"37777154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural mechanism of SKY-mediated regulation undefined\", \"How SKY state is physiologically controlled unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a non-GAP nuclear/DNA-damage role, with a 594-624 segment binding DNA-PKcs to promote its cytosolic retention.\",\n      \"evidence\": \"LC-MS/MS, Co-IP, \\u0394594-624 deletion, cardiac KO/KI mice, DNA damage assays\",\n      \"pmids\": [\"38045047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overlap of the DNA-PKcs and DRP1 binding regions not reconciled\", \"Mechanism of cytosolic retention undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected TBC1D15 to NOTCH1 stability and NUMB handling, blocking CDK8/CDK19 phosphodegron phosphorylation to prevent FBW7-mediated degradation.\",\n      \"evidence\": \"ChIP-seq, Co-IP, phosphorylation assays, hepatocyte triple-KO and PDX mouse models\",\n      \"pmids\": [\"38409448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TBC1D15 physically shields the phosphodegron unknown\", \"Relationship to mitochondrial functions unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a PLIN5-dependent mechanism by which TBC1D15 promotes mitochondria-lipid droplet contacts and fatty-acid \\u03b2-oxidation.\",\n      \"evidence\": \"Co-IP, domain mapping (10-180 aa), contact-site immunofluorescence, TEM, PKA inhibitor, hepatocyte overexpression mouse model\",\n      \"pmids\": [\"40334909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this is GAP-independent not formally tested\", \"Trigger for TBC1D15 mitochondrial translocation upon alcohol exposure undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Expanded TBC1D15's substrate range, showing it is also a GAP for the Arf-family GTPase Arl4D acting through its TBC domain.\",\n      \"evidence\": \"Co-IP, in vitro GAP assay, localization microscopy, knockdown with Arl4D activity readout\",\n      \"pmids\": [\"41709823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of dual Rab7/Arl4D selectivity unresolved\", \"Physiological balance between the two substrates unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how TBC1D15's GAP catalysis, its FIS1/DRP1 scaffolding at mitochondria, and its GAP-independent protein-stability roles (Numb-p53, NOTCH1, DNA-PKcs) are integrated within a single protein and which functions are coupled versus separable.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length structure showing how distinct functional modules coexist\", \"Whether GAP activity is required for scaffolding/protein-stability roles untested\", \"Tissue- and stimulus-specific selection among functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 17, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 9, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 8, 14, 16]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1, 9, 7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 8, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FIS1\", \"RAB7\", \"DRP1\", \"ATG8\", \"NUMB\", \"NOTCH1\", \"PLIN5\", \"ARL4D\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}