{"gene":"TRAPPC9","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2005,"finding":"NIBP/TRAPPC9 physically interacts with NIK and IKKβ (but not IKKα or IKKγ) via yeast two-hybrid and co-immunoprecipitation. Overexpression potentiates TNFα-induced NF-κB activation through increased phosphorylation of the IKK complex, IκBα, and p65; siRNA knockdown reduces TNFα-induced NF-κB activation, prevents NGF-induced neuronal differentiation, and decreases Bcl-xL expression in PC12 cells.","method":"Yeast two-hybrid screen, co-immunoprecipitation, overexpression/siRNA knockdown with NF-κB luciferase reporter, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, multiple functional assays (reporter, phosphorylation, differentiation) in one lab with orthogonal methods","pmids":["15951441"],"is_preprint":false},{"year":2005,"finding":"Yeast Trs120p (ortholog of TRAPPC9) is required for vesicle traffic from the early endosome to the late Golgi; trs120 mutants accumulate aberrant Berkeley body-like membrane structures and disrupt recycling of proteins through the early endosome. Trs120p colocalizes with the late Golgi marker Sec7p, and trs120 mutants display mislocalization of COPI subunits, implicating Trs120p in a COPI-dependent trafficking step on the early endosomal pathway.","method":"Yeast genetics (temperature-sensitive mutants), fluorescence microscopy, electron microscopy, colocalization with Sec7p and COPI subunits","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined trafficking phenotype, multiple orthogonal imaging methods, replicated across multiple alleles in yeast","pmids":["16314430"],"is_preprint":false},{"year":2011,"finding":"In mammalian cells, TRAPPC2 acts as an adaptor for TRAPPC9 in TRAPPII complex formation: TRAPPC2 binds TRAPPC9, which in turn binds TRAPPC10. A disease-causing TRAPPC2 mutation (D47Y) abolishes interaction with TRAPPC9, and deletional mutants of TRAPPC9 all fail to interact with TRAPPC2 and TRAPPC10. TRAPPC2 also binds TRAPPC8 (putative TRAPPIII-specific subunit), but endogenous TRAPPC9-positive TRAPPII does not contain TRAPPC8, indicating TRAPPC2 binds either TRAPPC9 or TRAPPC8 in the respective mammalian TRAPP complexes.","method":"Co-immunoprecipitation in mammalian cells with wild-type and disease-associated mutant constructs","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with multiple mutant constructs, single lab, two orthogonal mutation series","pmids":["21858081"],"is_preprint":false},{"year":2012,"finding":"TRAPPC9 directly binds p150Glued (dynactin subunit) via p150's carboxyl-terminal domain — the same domain that binds COPII coat components Sec23/Sec24. TRAPPC9 inhibits the interaction between p150Glued and Sec23/Sec24 both in vitro and in vivo, suggesting TRAPPC9 uncouples p150Glued from the COPII coat at the target membrane (ERGIC) to relay vesicle-dynactin interaction, allowing nascent ERGIC to continue microtubule-based movement.","method":"Co-immunoprecipitation, in vitro binding competition assay, overexpression-based competition for microtubule organizing center localization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding assay plus in vivo co-IP competition, single lab, two orthogonal methods","pmids":["22279557"],"is_preprint":false},{"year":2015,"finding":"Endogenous NIBP/TRAPPC9 binds specifically to phosphorylated IKK2 in a TNFα-dependent manner. NIBP knockdown transiently attenuates TNFα-stimulated phosphorylation of IKK2/p65 and degradation of IκBα, while NIBP overexpression enhances TNFα-induced NF-κB activation and inhibits apoptosis. NIBP knockdown inhibits growth, invasion, colony formation, and xenograft tumorigenesis of breast and colon cancer cells in an NF-κB-dependent manner.","method":"Co-immunoprecipitation of endogenous proteins, lentiviral shRNA knockdown, NF-κB luciferase reporter, xenograft mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous co-IP with phosphorylation-dependent binding, multiple cell-based functional assays and in vivo xenograft, single lab","pmids":["25704885"],"is_preprint":false},{"year":2013,"finding":"In mouse enteric neuronal cells, NIBP/TRAPPC9 shRNA knockdown inhibits TNFα-induced NF-κB activation and neuronal differentiation, while NIBP overexpression promotes both. NIBP-like immunoreactivity colocalizes with cholinergic (~98%) and nitrergic (~87%) neuronal markers in the myenteric plexus but not with glial, smooth muscle, or interstitial cells of Cajal markers.","method":"Lentiviral shRNA/overexpression in enteric neuronal cell line, NF-κB reporter assay, multi-label immunofluorescence/confocal microscopy in whole-mount intestine","journal":"Neurogastroenterology and motility","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown and overexpression with reporter assay plus detailed localization, single lab","pmids":["24011459"],"is_preprint":false},{"year":2020,"finding":"Trappc9-deficient mice exhibit cognitive/behavioral deficits and postnatal brain growth delay. Loss of Trappc9 compromises activation of Rab11 in brain, resulting in retardation of endocytic receptor recycling in neurons. An imbalance between dopamine D1 and D2 receptor-containing neurons in the striatum was found; pharmacological manipulation of dopamine receptors (D1 antagonist + D2 agonist) improved cognitive performance of Trappc9 null mice to wild-type levels.","method":"Trappc9 knockout mice, behavioral testing, biochemical Rab11-GTP pull-down assay, endocytic recycling assay in neurons, pharmacological rescue","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice with defined molecular mechanism (Rab11 activation assay), endocytic recycling readout, and pharmacological rescue across multiple orthogonal methods","pmids":["33208359"],"is_preprint":false},{"year":2020,"finding":"Trappc9 shows maternal allelic expression bias (~70%) in mouse brain. Heterozygous mice lacking the maternal allele (≈70% expression reduction) develop microcephaly, reduced exploratory activity, and social memory deficits similar to homozygous knockouts, while mice lacking the paternal allele (≈30% reduction) are phenotypically normal, establishing a dose-threshold effect linked to imprinting.","method":"Allele-specific expression analysis, Trappc9 knockout and heterozygous mouse models, MRI, behavioral testing, food intake measurement in a child with TRAPPC9 deficiency","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dose-threshold established via reciprocal heterozygotes with quantified allele expression, multiple phenotypic readouts, human case corroboration","pmids":["32877400"],"is_preprint":false},{"year":2019,"finding":"TRAPPC9 co-immunoprecipitates with L-plastin (LPL) in mature osteoclasts (confirmed by mass spectrometry and reciprocal co-IP). TRAPPC9 colocalizes with LPL at the periphery of osteoclasts. Overexpression of TRAPPC9 promotes LPL recruitment to the actin ring, reorganizes actin clusters, and regulates vinculin recruitment to the osteoclast periphery to initiate podosome formation.","method":"Co-immunoprecipitation followed by mass spectrometry, immunofluorescence colocalization, viral overexpression system in osteoclasts","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-confirmed binding partner, reciprocal co-IP, functional overexpression with cytoskeletal readout, single lab","pmids":["31453638"],"is_preprint":false},{"year":2022,"finding":"Patients with biallelic missense variants in TRAPPC9 present with an N-glycosylation defect (CDG type I pattern) in blood and fibroblasts. Tracer metabolomics in TRAPPC9-deficient fibroblasts revealed global metabolic changes including multiple glycosylation-related metabolites. Complementation with wild-type TRAPPC9 and immunofluorescence studies confirmed TRAPPC9 deficiency and abnormal localization, establishing that TRAPPC9 deficiency causes a congenital disorder of glycosylation.","method":"N-glycosylation analysis of patient blood/fibroblasts, tracer metabolomics, wild-type TRAPPC9 complementation, immunofluorescence localization in patient fibroblasts","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient fibroblast complementation with glycosylation biochemical readout and metabolomics, single lab, multiple orthogonal methods","pmids":["35042660"],"is_preprint":false},{"year":2022,"finding":"In TRAPPC9 variant (p.Phe232Leu) patient fibroblasts, mutant TRAPPC9 protein accumulates around the nucleus rather than displaying normal distribution. This disrupted localization reduces the amount of neutral lipid-carrying vesicles and their homogeneous distribution, linking abnormal TRAPPC9 localization to defective lipid vesicle trafficking.","method":"Immunostaining in patient fibroblasts, lipid droplet staining, western blotting, qRT-PCR","journal":"Journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient fibroblast study, single lab, localization and lipid droplet phenotype without mechanistic pathway dissection","pmids":["34983975"],"is_preprint":false},{"year":2023,"finding":"Nibp/Trappc9 deficiency in zebrafish (morpholino knockdown and CRISPR mutation) and mice (Cre/LoxP) impairs stability of the TRAPPII complex at actin filaments and microtubules of neurites and growth cones, resulting in defective elongation and branching of neuronal dendrites and axons without significant effects on neurite initiation or neural cell number/type.","method":"Morpholino knockdown in zebrafish, CRISPR/Cas9 mutation in zebrafish, Cre/LoxP knockout in mice, immunofluorescence of TRAPPII complex at cytoskeletal structures, neuronal morphometry","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent animal models (morpholino, CRISPR, conditional KO), direct visualization of TRAPPII-cytoskeletal association, specific morphological phenotype with mechanistic link to TRAPPII stability","pmids":["37416774"],"is_preprint":false},{"year":2024,"finding":"Trappc9-deficient mice have impaired dopamine synapse formation in the striatum: they synthesize dopamine normally but dopamine-secreting neurons have reduced abundance of dopamine-release structures. Combined transcriptomic (RNA-seq of DRD2 neurons) and proteomic (brain synaptosome) analyses show signs of impaired neurotransmitter secretion. Chronic treatment with DRD2 agonist quinpirole plus DRD1 antagonist SCH23390 relieved obesity and NAFLD; quinpirole alone restored blood glucose homeostasis.","method":"Trappc9 KO mice, RNA-sequencing, proteomics of synaptosomes, histological and biochemical examination of dopamine synaptic structures, pharmacological rescue","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics plus histology and pharmacological rescue in KO mice, single lab","pmids":["38889014"],"is_preprint":false},{"year":2024,"finding":"Leishmania upregulates host TRAPPC9 (the GEF for Rab18) and Rab18 expression in macrophages by reducing Dicer via gp63 metalloprotease, thereby downregulating miR-1914-3p which normally suppresses both TRAPPC9 and Rab18. This results in recruitment of lipid bodies to Leishmania-containing parasitophorous vacuoles and acquisition of host fatty acids for parasite growth; overexpression of miR-1914-3p blocks LB recruitment and suppresses parasite multiplication.","method":"miRNA overexpression/inhibition, Dicer knockdown, miR-1914-3p reporter assays, lipid body imaging, fatty acid transfer assay in macrophages","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional identification of TRAPPC9 as Rab18 GEF in this context with multiple mechanistic steps validated, single lab","pmids":["38412149"],"is_preprint":false},{"year":2024,"finding":"Trappc9-deficient primary hippocampal neurons accumulate a larger lipid droplet (LD) volume per cell following oleic acid stimulation, with markedly reduced Perilipin-2 coating of LDs, implicating the TRAPPII-Rab18 axis in neuronal LD homeostasis. In vivo, Trappc9 KO mice show disproportionate hippocampal volume reduction associated with loss of Sox2-positive neural stem/progenitor cells.","method":"Trappc9 KO mice, in vivo MRI, immunofluorescence (Sox2, Perilipin-2), lipid droplet staining in primary hippocampal neurons","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with in vivo imaging and cellular mechanistic readout, single lab, multiple orthogonal methods","pmids":["38331351"],"is_preprint":false},{"year":2017,"finding":"NIBP/TRAPPC9 knockdown in HCT116 colorectal cancer cells reduces phosphorylation of p65, IκBα, IκBβ, ERK1/2, and JNK1/2 following TNFα stimulation, but does not affect basal p-ERK1/2 in the absence of TNFα stimulation. This places NIBP in the canonical NF-κB pathway and indicates it also modulates TNFα-induced MAPK (ERK/JNK) signaling.","method":"Lentiviral shRNA knockdown in HCT116 cells, western blotting of pathway components after TNFα stimulation, in vivo orthotopic xenograft","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown with defined signaling readouts and in vivo validation, single lab","pmids":["28125661"],"is_preprint":false},{"year":2022,"finding":"Trappc9-null adipose-derived stem cells (ASCs) exhibit premature senescence, preferential adipogenic differentiation, profound lipid droplet accumulation in adipogenic cells, and altered calcium deposition in osteoblasts. Trappc9 deficiency upregulates expression of Rab1, Rab11, and Rab18, and agitates autophagy in ASCs. Neural stem cell content in the subventricular zone and dentate gyrus is vastly reduced in Trappc9-null mice.","method":"Isolation and in vitro differentiation of ASCs from Trappc9 KO mice, western blotting (Rab proteins, autophagy markers), immunofluorescence of neural stem cells in KO brain","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO-derived primary cells with multiple biochemical and morphological readouts, single lab","pmids":["35563289"],"is_preprint":false}],"current_model":"TRAPPC9 (NIBP) is a TRAPPII complex subunit that functions as a GEF-scaffold bridging intracellular vesicle trafficking and NF-κB signaling: it physically binds NIK and phospho-IKKβ to potentiate TNFα-induced NF-κB activation; acts downstream as the GEF for Rab11 and Rab18 to regulate endocytic receptor recycling, lipid droplet homeostasis, and ER-to-Golgi/endosome-to-Golgi traffic; binds p150Glued dynactin to relay COPII vesicle transport along microtubules; and, through TRAPPC2 as adaptor, integrates into the mammalian TRAPPII complex where it is required for neurite elongation/branching, neural stem cell maintenance, and dopamine synapse formation, explaining why loss-of-function mutations cause microcephaly, intellectual disability, and obesity."},"narrative":{"mechanistic_narrative":"TRAPPC9 (NIBP) is a multifunctional protein that bridges intracellular membrane trafficking with NF-κB signaling and is essential for nervous system development [PMID:15951441, PMID:33208359]. As a subunit of the mammalian TRAPPII complex, it is incorporated through TRAPPC2, which acts as an adaptor linking TRAPPC9 to TRAPPC10; disease-associated mutations in either TRAPPC2 or TRAPPC9 abolish this assembly [PMID:21858081]. The conserved trafficking role of TRAPPC9 traces to its yeast ortholog Trs120p, which mediates COPI-dependent vesicle traffic from the early endosome to the late Golgi [PMID:16314430]. In mammals TRAPPC9 functions as a guanine-nucleotide exchange factor activating Rab11 to drive endocytic receptor recycling in neurons and Rab18 to govern lipid droplet homeostasis, controlling lipid body recruitment and lipid droplet coating [PMID:33208359, PMID:38412149, PMID:38331351]; it also binds the dynactin subunit p150Glued through the same domain p150 uses to engage the COPII components Sec23/Sec24, competitively uncoupling vesicles from the coat to relay microtubule-based transport [PMID:22279557]. In parallel, TRAPPC9 binds NIK and phosphorylated IKKβ to potentiate TNFα-induced canonical NF-κB activation, promoting phosphorylation of IKK, IκBα and p65 and influencing neuronal differentiation and tumor cell survival [PMID:15951441, PMID:25704885, PMID:28125661]. Loss of TRAPPC9 destabilizes the TRAPPII complex at neurite and growth-cone cytoskeleton, impairing dendritic and axonal elongation and branching, depleting Sox2-positive neural stem/progenitor cells, and disrupting striatal dopamine synapse formation [PMID:37416774, PMID:38331351, PMID:38889014]. These deficits underlie a dose-sensitive, imprinting-linked neurodevelopmental disorder with microcephaly and obesity [PMID:32877400], and biallelic TRAPPC9 variants additionally manifest as a congenital disorder of glycosylation [PMID:35042660].","teleology":[{"year":2005,"claim":"Established that TRAPPC9 is a signaling scaffold by showing it physically links NIK and IKKβ to potentiate NF-κB activation, defining a function distinct from generic trafficking.","evidence":"Yeast two-hybrid, reciprocal co-IP, and NF-κB reporter/phosphorylation assays in PC12 cells","pmids":["15951441"],"confidence":"High","gaps":["Whether NF-κB scaffolding is independent of the TRAPPII trafficking role was not resolved","Direct kinase activation mechanism not defined"]},{"year":2005,"claim":"Defined the conserved trafficking function via the yeast ortholog Trs120p, placing TRAPPC9 at a COPI-dependent endosome-to-late-Golgi step.","evidence":"Temperature-sensitive yeast mutants, fluorescence/electron microscopy, colocalization with Sec7p and COPI","pmids":["16314430"],"confidence":"High","gaps":["Yeast trafficking step not directly demonstrated for mammalian TRAPPC9","GEF substrate in yeast not identified here"]},{"year":2011,"claim":"Resolved how TRAPPC9 assembles into the mammalian TRAPPII complex, showing TRAPPC2 is the adaptor that bridges TRAPPC9 to TRAPPC10 and that disease mutations disrupt this.","evidence":"Co-IP in mammalian cells with wild-type and disease-mutant constructs","pmids":["21858081"],"confidence":"Medium","gaps":["Single lab; stoichiometry and structure of the assembled complex not determined","Functional consequence of assembly on GEF activity untested"]},{"year":2012,"claim":"Connected TRAPPC9 to microtubule-based vesicle transport by showing it competes with COPII for p150Glued binding, providing a handoff mechanism from coat to dynactin.","evidence":"Co-IP, in vitro binding competition, MTOC localization competition assays","pmids":["22279557"],"confidence":"Medium","gaps":["In vivo relevance to physiological transport not established","Single lab"]},{"year":2013,"claim":"Showed the NF-κB/differentiation function operates in a defined neuronal population, mapping TRAPPC9 to cholinergic and nitrergic enteric neurons.","evidence":"shRNA/overexpression in enteric neuronal line with NF-κB reporter; multi-label immunofluorescence in whole-mount intestine","pmids":["24011459"],"confidence":"Medium","gaps":["Causal link between enteric NF-κB role and organismal phenotype not tested"]},{"year":2015,"claim":"Confirmed phosphorylation-dependent, endogenous binding of TRAPPC9 to active IKK2 and extended the NF-κB role to tumor growth and survival.","evidence":"Endogenous co-IP, shRNA knockdown, NF-κB reporter, xenograft tumor models","pmids":["25704885"],"confidence":"Medium","gaps":["Direct enzymatic mechanism on IKK2 not defined","Single lab"]},{"year":2017,"claim":"Broadened the signaling output by showing TRAPPC9 also modulates TNFα-induced MAPK (ERK/JNK) phosphorylation alongside canonical NF-κB.","evidence":"shRNA knockdown in HCT116 cells, pathway western blotting after TNFα, orthotopic xenograft","pmids":["28125661"],"confidence":"Medium","gaps":["Mechanism connecting TRAPPC9 to MAPK branch unknown","Single lab"]},{"year":2020,"claim":"Established the in vivo GEF function and disease mechanism: TRAPPC9 loss impairs Rab11 activation and endocytic recycling, producing brain growth and cognitive deficits reversible by dopamine receptor manipulation.","evidence":"Trappc9 KO mice, Rab11-GTP pull-down, neuronal recycling assay, pharmacological rescue","pmids":["33208359"],"confidence":"High","gaps":["Direct GEF catalysis on Rab11 not reconstituted biochemically","How recycling defect leads to dopamine receptor imbalance unresolved"]},{"year":2020,"claim":"Defined the genetics of disease severity, showing maternal-biased imprinted expression creates a dose-threshold whereby maternal allele loss recapitulates the knockout phenotype.","evidence":"Allele-specific expression, reciprocal heterozygous and KO mice, MRI, behavior, human case","pmids":["32877400"],"confidence":"High","gaps":["Imprinting control region/regulatory mechanism not mapped","Conservation of imprinting in humans not fully established"]},{"year":2019,"claim":"Identified a cytoskeletal partner, showing TRAPPC9 binds L-plastin and organizes actin and podosome formation in osteoclasts.","evidence":"Co-IP/mass spectrometry, reciprocal co-IP, immunofluorescence, overexpression in osteoclasts","pmids":["31453638"],"confidence":"Medium","gaps":["Relationship of L-plastin binding to TRAPPII GEF function unknown","Single lab, overexpression-based"]},{"year":2022,"claim":"Linked TRAPPC9 deficiency to a congenital disorder of glycosylation, expanding its phenotypic spectrum to a metabolic defect.","evidence":"Patient N-glycosylation analysis, tracer metabolomics, wild-type complementation, immunofluorescence in fibroblasts","pmids":["35042660"],"confidence":"Medium","gaps":["Mechanistic route from trafficking defect to glycosylation abnormality not defined"]},{"year":2022,"claim":"Connected TRAPPC9 to stem cell maintenance and lipid/adipogenic homeostasis, showing KO causes premature senescence, lipid droplet accumulation, altered Rab expression and autophagy, and neural stem cell depletion.","evidence":"Trappc9 KO ASC differentiation, western blotting of Rab and autophagy markers, neural stem cell immunofluorescence","pmids":["35563289"],"confidence":"Medium","gaps":["Causal ordering of senescence, Rab upregulation and autophagy not resolved","Single lab"]},{"year":2024,"claim":"Defined the Rab18-dependent lipid droplet role in neurons, showing TRAPPC9 loss enlarges LDs, reduces Perilipin-2 coating, and depletes hippocampal neural stem cells.","evidence":"Trappc9 KO mice, MRI, lipid droplet staining in primary hippocampal neurons, Sox2/Perilipin-2 immunofluorescence","pmids":["38331351"],"confidence":"Medium","gaps":["Direct GEF activity toward Rab18 not biochemically reconstituted here","Link between LD defect and stem cell loss correlative"]},{"year":2024,"claim":"Refined the neurodevelopmental and metabolic phenotype, showing TRAPPC9 is required for dopamine synapse/release structure formation and that dopamine receptor pharmacology relieves obesity and NAFLD.","evidence":"Trappc9 KO mice, RNA-seq of DRD2 neurons, synaptosome proteomics, histology, pharmacological rescue","pmids":["38889014"],"confidence":"Medium","gaps":["Molecular link between trafficking defect and reduced release structures unclear","Single lab"]},{"year":2024,"claim":"Demonstrated functional exploitation of the TRAPPC9-Rab18 axis by a pathogen, with Leishmania upregulating TRAPPC9/Rab18 via miR-1914-3p suppression to recruit host lipid bodies.","evidence":"miRNA over/inhibition, Dicer knockdown, reporter assays, lipid body imaging and fatty acid transfer in macrophages","pmids":["38412149"],"confidence":"Medium","gaps":["Direct GEF assay on Rab18 not performed in this context","Generalizability beyond Leishmania infection unknown"]},{"year":null,"claim":"How TRAPPC9's distinct activities — NF-κB scaffolding, Rab GEF function, and cytoskeletal/dynactin coupling — are mechanistically coordinated within or independent of the TRAPPII complex remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted biochemistry confirming TRAPPC9 catalyzes Rab11/Rab18 nucleotide exchange","No structure of the mammalian TRAPPII complex containing TRAPPC9","Whether NF-κB and trafficking functions use the same molecular surface unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,13,0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,8,11]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[11,8]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,3,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,6,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,9]}],"complexes":["TRAPPII complex"],"partners":["TRAPPC2","TRAPPC10","NIK","IKBKB","DCTN1","LCP1","RAB11","RAB18"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96Q05","full_name":"Trafficking protein particle complex subunit 9","aliases":["NIK- and IKBKB-binding protein","Tularik gene 1 protein"],"length_aa":1148,"mass_kda":128.5,"function":"Functions as an activator of NF-kappa-B through increased phosphorylation of the IKK complex. May function in neuronal cells differentiation. May play a role in vesicular transport from endoplasmic reticulum to Golgi","subcellular_location":"Golgi apparatus, cis-Golgi network; Endoplasmic reticulum; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96Q05/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRAPPC9","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TRAPPC1","stoichiometry":0.2},{"gene":"TRAPPC2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRAPPC9","total_profiled":1310},"omim":[{"mim_id":"621140","title":"CONGENITAL DISORDER OF GLYCOSYLATION TYPE 1EE WITH OR WITHOUT IMMUNODEFICIENCY; CDG1EE","url":"https://www.omim.org/entry/621140"},{"mim_id":"618899","title":"MANNOSIDASE, ALPHA, CLASS 2B, MEMBER 2; MAN2B2","url":"https://www.omim.org/entry/618899"},{"mim_id":"614459","title":"TRANSMEMBRANE PROTEIN 138; TMEM138","url":"https://www.omim.org/entry/614459"},{"mim_id":"613277","title":"TRANSMEMBRANE PROTEIN 216; TMEM216","url":"https://www.omim.org/entry/613277"},{"mim_id":"613192","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 13; MRT13","url":"https://www.omim.org/entry/613192"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRAPPC9"},"hgnc":{"alias_symbol":["IKBKBBP","NIBP","KIAA1882","T1","TRS120","MRT13"],"prev_symbol":[]},"alphafold":{"accession":"Q96Q05","domains":[{"cath_id":"3.40.50,3.40.50","chopping":"11-169","consensus_level":"high","plddt":90.5602,"start":11,"end":169},{"cath_id":"-","chopping":"441-533","consensus_level":"medium","plddt":91.5459,"start":441,"end":533},{"cath_id":"2.60.40,2.60.40","chopping":"540-559_588-692","consensus_level":"high","plddt":91.5122,"start":540,"end":692},{"cath_id":"2.60.40.10","chopping":"700-803_851-883","consensus_level":"high","plddt":86.55,"start":700,"end":883},{"cath_id":"2.60.40.10","chopping":"1015-1145","consensus_level":"high","plddt":82.2274,"start":1015,"end":1145},{"cath_id":"2.60.40","chopping":"888-950_966-1010","consensus_level":"high","plddt":84.4972,"start":888,"end":1010}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q05","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q05-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q05-F1-predicted_aligned_error_v6.png","plddt_mean":82.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRAPPC9","jax_strain_url":"https://www.jax.org/strain/search?query=TRAPPC9"},"sequence":{"accession":"Q96Q05","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96Q05.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96Q05/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q05"}},"corpus_meta":[{"pmid":"20004763","id":"PMC_20004763","title":"A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20004763","citation_count":123,"is_preprint":false},{"pmid":"20004765","id":"PMC_20004765","title":"Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20004765","citation_count":114,"is_preprint":false},{"pmid":"16314430","id":"PMC_16314430","title":"Mutants in trs120 disrupt traffic from the early endosome to the late Golgi.","date":"2005","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16314430","citation_count":106,"is_preprint":false},{"pmid":"15951441","id":"PMC_15951441","title":"NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15951441","citation_count":104,"is_preprint":false},{"pmid":"22549410","id":"PMC_22549410","title":"TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype.","date":"2012","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/22549410","citation_count":62,"is_preprint":false},{"pmid":"21858081","id":"PMC_21858081","title":"The adaptor function of TRAPPC2 in mammalian TRAPPs explains TRAPPC2-associated SEDT and TRAPPC9-associated congenital intellectual disability.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21858081","citation_count":54,"is_preprint":false},{"pmid":"22989526","id":"PMC_22989526","title":"A homozygous splice site mutation in TRAPPC9 causes intellectual disability and microcephaly.","date":"2012","source":"European 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Mutations in the TRAPPC9 Gene Reveal a Connection of Non-syndromic Intellectual Disability and Autism Spectrum Disorder.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33719327","citation_count":17,"is_preprint":false},{"pmid":"35042660","id":"PMC_35042660","title":"TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability.","date":"2022","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35042660","citation_count":16,"is_preprint":false},{"pmid":"36213405","id":"PMC_36213405","title":"Genetic polymorphisms of TRAPPC9 and CD4 genes and their association with milk production and mastitis resistance phenotypic traits in Chinese Holstein.","date":"2022","source":"Frontiers in veterinary 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Iran.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33513295","citation_count":9,"is_preprint":false},{"pmid":"35563289","id":"PMC_35563289","title":"Trappc9 Deficiency Impairs the Plasticity of Stem Cells.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35563289","citation_count":8,"is_preprint":false},{"pmid":"34737153","id":"PMC_34737153","title":"Further insights into the spectrum phenotype of TRAPPC9 and CDK5RAP2 genes, segregating independently in a large Tunisian family with intellectual disability and microcephaly.","date":"2021","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34737153","citation_count":6,"is_preprint":false},{"pmid":"37416774","id":"PMC_37416774","title":"Defective neurite elongation and branching in Nibp/Trappc9 deficient zebrafish and mice.","date":"2023","source":"International journal of biological 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syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/38058760","citation_count":5,"is_preprint":false},{"pmid":"36574751","id":"PMC_36574751","title":"TRAPPC9-related neurodevelopmental disorder: Report of a homozygous deletion in TRAPPC9 due to paternal uniparental isodisomy.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36574751","citation_count":5,"is_preprint":false},{"pmid":"39828627","id":"PMC_39828627","title":"Chromium-Doped NiBP Micro-Sphere Electrocatalysts for Green Hydrogen Production under Industrial Operational Conditions.","date":"2025","source":"Small methods","url":"https://pubmed.ncbi.nlm.nih.gov/39828627","citation_count":5,"is_preprint":false},{"pmid":"38889014","id":"PMC_38889014","title":"Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in Trappc9-linked brain developmental syndrome.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/38889014","citation_count":4,"is_preprint":false},{"pmid":"36313557","id":"PMC_36313557","title":"Variable allelic expression of imprinted genes at the Peg13, Trappc9, Ago2 cluster in single neural cells.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36313557","citation_count":4,"is_preprint":false},{"pmid":"38467738","id":"PMC_38467738","title":"Expanding the genetic and phenotypic spectrum of TRAPPC9 and MID2-related neurodevelopmental disabilities: report of two novel mutations, 3D-modelling, and molecular docking studies.","date":"2024","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38467738","citation_count":3,"is_preprint":false},{"pmid":"38331351","id":"PMC_38331351","title":"Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms in Trappc9 KO mice.","date":"2024","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38331351","citation_count":2,"is_preprint":false},{"pmid":"39261946","id":"PMC_39261946","title":"Overexpression of ZFP69B promotes hepatocellular carcinoma growth by upregulating the expression of TLX1 and TRAPPC9.","date":"2024","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/39261946","citation_count":2,"is_preprint":false},{"pmid":"39184350","id":"PMC_39184350","title":"Case Report: Whole exome sequencing identifies compound heterozygous variants in the TRAPPC9 gene in a child with developmental delay.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39184350","citation_count":2,"is_preprint":false},{"pmid":"31966720","id":"PMC_31966720","title":"Expression of NIBP and its clinical significance in human early colorectal cancer.","date":"2017","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31966720","citation_count":1,"is_preprint":false},{"pmid":"41300827","id":"PMC_41300827","title":"Canine Neuronal Ceroid Lipofuscinosis-like Disorder Associated with Sequence Variants in AP3B1 and TRAPPC9.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41300827","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26064,"output_tokens":4975,"usd":0.076409,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13346,"output_tokens":4799,"usd":0.093353,"stage2_stop_reason":"end_turn"},"total_usd":0.169762,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"NIBP/TRAPPC9 physically interacts with NIK and IKKβ (but not IKKα or IKKγ) via yeast two-hybrid and co-immunoprecipitation. Overexpression potentiates TNFα-induced NF-κB activation through increased phosphorylation of the IKK complex, IκBα, and p65; siRNA knockdown reduces TNFα-induced NF-κB activation, prevents NGF-induced neuronal differentiation, and decreases Bcl-xL expression in PC12 cells.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, overexpression/siRNA knockdown with NF-κB luciferase reporter, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, multiple functional assays (reporter, phosphorylation, differentiation) in one lab with orthogonal methods\",\n      \"pmids\": [\"15951441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Yeast Trs120p (ortholog of TRAPPC9) is required for vesicle traffic from the early endosome to the late Golgi; trs120 mutants accumulate aberrant Berkeley body-like membrane structures and disrupt recycling of proteins through the early endosome. Trs120p colocalizes with the late Golgi marker Sec7p, and trs120 mutants display mislocalization of COPI subunits, implicating Trs120p in a COPI-dependent trafficking step on the early endosomal pathway.\",\n      \"method\": \"Yeast genetics (temperature-sensitive mutants), fluorescence microscopy, electron microscopy, colocalization with Sec7p and COPI subunits\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined trafficking phenotype, multiple orthogonal imaging methods, replicated across multiple alleles in yeast\",\n      \"pmids\": [\"16314430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In mammalian cells, TRAPPC2 acts as an adaptor for TRAPPC9 in TRAPPII complex formation: TRAPPC2 binds TRAPPC9, which in turn binds TRAPPC10. A disease-causing TRAPPC2 mutation (D47Y) abolishes interaction with TRAPPC9, and deletional mutants of TRAPPC9 all fail to interact with TRAPPC2 and TRAPPC10. TRAPPC2 also binds TRAPPC8 (putative TRAPPIII-specific subunit), but endogenous TRAPPC9-positive TRAPPII does not contain TRAPPC8, indicating TRAPPC2 binds either TRAPPC9 or TRAPPC8 in the respective mammalian TRAPP complexes.\",\n      \"method\": \"Co-immunoprecipitation in mammalian cells with wild-type and disease-associated mutant constructs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with multiple mutant constructs, single lab, two orthogonal mutation series\",\n      \"pmids\": [\"21858081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRAPPC9 directly binds p150Glued (dynactin subunit) via p150's carboxyl-terminal domain — the same domain that binds COPII coat components Sec23/Sec24. TRAPPC9 inhibits the interaction between p150Glued and Sec23/Sec24 both in vitro and in vivo, suggesting TRAPPC9 uncouples p150Glued from the COPII coat at the target membrane (ERGIC) to relay vesicle-dynactin interaction, allowing nascent ERGIC to continue microtubule-based movement.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding competition assay, overexpression-based competition for microtubule organizing center localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding assay plus in vivo co-IP competition, single lab, two orthogonal methods\",\n      \"pmids\": [\"22279557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Endogenous NIBP/TRAPPC9 binds specifically to phosphorylated IKK2 in a TNFα-dependent manner. NIBP knockdown transiently attenuates TNFα-stimulated phosphorylation of IKK2/p65 and degradation of IκBα, while NIBP overexpression enhances TNFα-induced NF-κB activation and inhibits apoptosis. NIBP knockdown inhibits growth, invasion, colony formation, and xenograft tumorigenesis of breast and colon cancer cells in an NF-κB-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, lentiviral shRNA knockdown, NF-κB luciferase reporter, xenograft mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous co-IP with phosphorylation-dependent binding, multiple cell-based functional assays and in vivo xenograft, single lab\",\n      \"pmids\": [\"25704885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In mouse enteric neuronal cells, NIBP/TRAPPC9 shRNA knockdown inhibits TNFα-induced NF-κB activation and neuronal differentiation, while NIBP overexpression promotes both. NIBP-like immunoreactivity colocalizes with cholinergic (~98%) and nitrergic (~87%) neuronal markers in the myenteric plexus but not with glial, smooth muscle, or interstitial cells of Cajal markers.\",\n      \"method\": \"Lentiviral shRNA/overexpression in enteric neuronal cell line, NF-κB reporter assay, multi-label immunofluorescence/confocal microscopy in whole-mount intestine\",\n      \"journal\": \"Neurogastroenterology and motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown and overexpression with reporter assay plus detailed localization, single lab\",\n      \"pmids\": [\"24011459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Trappc9-deficient mice exhibit cognitive/behavioral deficits and postnatal brain growth delay. Loss of Trappc9 compromises activation of Rab11 in brain, resulting in retardation of endocytic receptor recycling in neurons. An imbalance between dopamine D1 and D2 receptor-containing neurons in the striatum was found; pharmacological manipulation of dopamine receptors (D1 antagonist + D2 agonist) improved cognitive performance of Trappc9 null mice to wild-type levels.\",\n      \"method\": \"Trappc9 knockout mice, behavioral testing, biochemical Rab11-GTP pull-down assay, endocytic recycling assay in neurons, pharmacological rescue\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice with defined molecular mechanism (Rab11 activation assay), endocytic recycling readout, and pharmacological rescue across multiple orthogonal methods\",\n      \"pmids\": [\"33208359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Trappc9 shows maternal allelic expression bias (~70%) in mouse brain. Heterozygous mice lacking the maternal allele (≈70% expression reduction) develop microcephaly, reduced exploratory activity, and social memory deficits similar to homozygous knockouts, while mice lacking the paternal allele (≈30% reduction) are phenotypically normal, establishing a dose-threshold effect linked to imprinting.\",\n      \"method\": \"Allele-specific expression analysis, Trappc9 knockout and heterozygous mouse models, MRI, behavioral testing, food intake measurement in a child with TRAPPC9 deficiency\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dose-threshold established via reciprocal heterozygotes with quantified allele expression, multiple phenotypic readouts, human case corroboration\",\n      \"pmids\": [\"32877400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAPPC9 co-immunoprecipitates with L-plastin (LPL) in mature osteoclasts (confirmed by mass spectrometry and reciprocal co-IP). TRAPPC9 colocalizes with LPL at the periphery of osteoclasts. Overexpression of TRAPPC9 promotes LPL recruitment to the actin ring, reorganizes actin clusters, and regulates vinculin recruitment to the osteoclast periphery to initiate podosome formation.\",\n      \"method\": \"Co-immunoprecipitation followed by mass spectrometry, immunofluorescence colocalization, viral overexpression system in osteoclasts\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-confirmed binding partner, reciprocal co-IP, functional overexpression with cytoskeletal readout, single lab\",\n      \"pmids\": [\"31453638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Patients with biallelic missense variants in TRAPPC9 present with an N-glycosylation defect (CDG type I pattern) in blood and fibroblasts. Tracer metabolomics in TRAPPC9-deficient fibroblasts revealed global metabolic changes including multiple glycosylation-related metabolites. Complementation with wild-type TRAPPC9 and immunofluorescence studies confirmed TRAPPC9 deficiency and abnormal localization, establishing that TRAPPC9 deficiency causes a congenital disorder of glycosylation.\",\n      \"method\": \"N-glycosylation analysis of patient blood/fibroblasts, tracer metabolomics, wild-type TRAPPC9 complementation, immunofluorescence localization in patient fibroblasts\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient fibroblast complementation with glycosylation biochemical readout and metabolomics, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35042660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In TRAPPC9 variant (p.Phe232Leu) patient fibroblasts, mutant TRAPPC9 protein accumulates around the nucleus rather than displaying normal distribution. This disrupted localization reduces the amount of neutral lipid-carrying vesicles and their homogeneous distribution, linking abnormal TRAPPC9 localization to defective lipid vesicle trafficking.\",\n      \"method\": \"Immunostaining in patient fibroblasts, lipid droplet staining, western blotting, qRT-PCR\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient fibroblast study, single lab, localization and lipid droplet phenotype without mechanistic pathway dissection\",\n      \"pmids\": [\"34983975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nibp/Trappc9 deficiency in zebrafish (morpholino knockdown and CRISPR mutation) and mice (Cre/LoxP) impairs stability of the TRAPPII complex at actin filaments and microtubules of neurites and growth cones, resulting in defective elongation and branching of neuronal dendrites and axons without significant effects on neurite initiation or neural cell number/type.\",\n      \"method\": \"Morpholino knockdown in zebrafish, CRISPR/Cas9 mutation in zebrafish, Cre/LoxP knockout in mice, immunofluorescence of TRAPPII complex at cytoskeletal structures, neuronal morphometry\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent animal models (morpholino, CRISPR, conditional KO), direct visualization of TRAPPII-cytoskeletal association, specific morphological phenotype with mechanistic link to TRAPPII stability\",\n      \"pmids\": [\"37416774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Trappc9-deficient mice have impaired dopamine synapse formation in the striatum: they synthesize dopamine normally but dopamine-secreting neurons have reduced abundance of dopamine-release structures. Combined transcriptomic (RNA-seq of DRD2 neurons) and proteomic (brain synaptosome) analyses show signs of impaired neurotransmitter secretion. Chronic treatment with DRD2 agonist quinpirole plus DRD1 antagonist SCH23390 relieved obesity and NAFLD; quinpirole alone restored blood glucose homeostasis.\",\n      \"method\": \"Trappc9 KO mice, RNA-sequencing, proteomics of synaptosomes, histological and biochemical examination of dopamine synaptic structures, pharmacological rescue\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics plus histology and pharmacological rescue in KO mice, single lab\",\n      \"pmids\": [\"38889014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Leishmania upregulates host TRAPPC9 (the GEF for Rab18) and Rab18 expression in macrophages by reducing Dicer via gp63 metalloprotease, thereby downregulating miR-1914-3p which normally suppresses both TRAPPC9 and Rab18. This results in recruitment of lipid bodies to Leishmania-containing parasitophorous vacuoles and acquisition of host fatty acids for parasite growth; overexpression of miR-1914-3p blocks LB recruitment and suppresses parasite multiplication.\",\n      \"method\": \"miRNA overexpression/inhibition, Dicer knockdown, miR-1914-3p reporter assays, lipid body imaging, fatty acid transfer assay in macrophages\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional identification of TRAPPC9 as Rab18 GEF in this context with multiple mechanistic steps validated, single lab\",\n      \"pmids\": [\"38412149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Trappc9-deficient primary hippocampal neurons accumulate a larger lipid droplet (LD) volume per cell following oleic acid stimulation, with markedly reduced Perilipin-2 coating of LDs, implicating the TRAPPII-Rab18 axis in neuronal LD homeostasis. In vivo, Trappc9 KO mice show disproportionate hippocampal volume reduction associated with loss of Sox2-positive neural stem/progenitor cells.\",\n      \"method\": \"Trappc9 KO mice, in vivo MRI, immunofluorescence (Sox2, Perilipin-2), lipid droplet staining in primary hippocampal neurons\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with in vivo imaging and cellular mechanistic readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38331351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NIBP/TRAPPC9 knockdown in HCT116 colorectal cancer cells reduces phosphorylation of p65, IκBα, IκBβ, ERK1/2, and JNK1/2 following TNFα stimulation, but does not affect basal p-ERK1/2 in the absence of TNFα stimulation. This places NIBP in the canonical NF-κB pathway and indicates it also modulates TNFα-induced MAPK (ERK/JNK) signaling.\",\n      \"method\": \"Lentiviral shRNA knockdown in HCT116 cells, western blotting of pathway components after TNFα stimulation, in vivo orthotopic xenograft\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown with defined signaling readouts and in vivo validation, single lab\",\n      \"pmids\": [\"28125661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Trappc9-null adipose-derived stem cells (ASCs) exhibit premature senescence, preferential adipogenic differentiation, profound lipid droplet accumulation in adipogenic cells, and altered calcium deposition in osteoblasts. Trappc9 deficiency upregulates expression of Rab1, Rab11, and Rab18, and agitates autophagy in ASCs. Neural stem cell content in the subventricular zone and dentate gyrus is vastly reduced in Trappc9-null mice.\",\n      \"method\": \"Isolation and in vitro differentiation of ASCs from Trappc9 KO mice, western blotting (Rab proteins, autophagy markers), immunofluorescence of neural stem cells in KO brain\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO-derived primary cells with multiple biochemical and morphological readouts, single lab\",\n      \"pmids\": [\"35563289\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRAPPC9 (NIBP) is a TRAPPII complex subunit that functions as a GEF-scaffold bridging intracellular vesicle trafficking and NF-κB signaling: it physically binds NIK and phospho-IKKβ to potentiate TNFα-induced NF-κB activation; acts downstream as the GEF for Rab11 and Rab18 to regulate endocytic receptor recycling, lipid droplet homeostasis, and ER-to-Golgi/endosome-to-Golgi traffic; binds p150Glued dynactin to relay COPII vesicle transport along microtubules; and, through TRAPPC2 as adaptor, integrates into the mammalian TRAPPII complex where it is required for neurite elongation/branching, neural stem cell maintenance, and dopamine synapse formation, explaining why loss-of-function mutations cause microcephaly, intellectual disability, and obesity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRAPPC9 (NIBP) is a multifunctional protein that bridges intracellular membrane trafficking with NF-\\u03baB signaling and is essential for nervous system development [#0, #6]. As a subunit of the mammalian TRAPPII complex, it is incorporated through TRAPPC2, which acts as an adaptor linking TRAPPC9 to TRAPPC10; disease-associated mutations in either TRAPPC2 or TRAPPC9 abolish this assembly [#2]. The conserved trafficking role of TRAPPC9 traces to its yeast ortholog Trs120p, which mediates COPI-dependent vesicle traffic from the early endosome to the late Golgi [#1]. In mammals TRAPPC9 functions as a guanine-nucleotide exchange factor activating Rab11 to drive endocytic receptor recycling in neurons and Rab18 to govern lipid droplet homeostasis, controlling lipid body recruitment and lipid droplet coating [#6, #13, #14]; it also binds the dynactin subunit p150Glued through the same domain p150 uses to engage the COPII components Sec23/Sec24, competitively uncoupling vesicles from the coat to relay microtubule-based transport [#3]. In parallel, TRAPPC9 binds NIK and phosphorylated IKK\\u03b2 to potentiate TNF\\u03b1-induced canonical NF-\\u03baB activation, promoting phosphorylation of IKK, I\\u03baB\\u03b1 and p65 and influencing neuronal differentiation and tumor cell survival [#0, #4, #15]. Loss of TRAPPC9 destabilizes the TRAPPII complex at neurite and growth-cone cytoskeleton, impairing dendritic and axonal elongation and branching, depleting Sox2-positive neural stem/progenitor cells, and disrupting striatal dopamine synapse formation [#11, #14, #12]. These deficits underlie a dose-sensitive, imprinting-linked neurodevelopmental disorder with microcephaly and obesity [#7], and biallelic TRAPPC9 variants additionally manifest as a congenital disorder of glycosylation [#9].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that TRAPPC9 is a signaling scaffold by showing it physically links NIK and IKK\\u03b2 to potentiate NF-\\u03baB activation, defining a function distinct from generic trafficking.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, and NF-\\u03baB reporter/phosphorylation assays in PC12 cells\",\n      \"pmids\": [\"15951441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NF-\\u03baB scaffolding is independent of the TRAPPII trafficking role was not resolved\", \"Direct kinase activation mechanism not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the conserved trafficking function via the yeast ortholog Trs120p, placing TRAPPC9 at a COPI-dependent endosome-to-late-Golgi step.\",\n      \"evidence\": \"Temperature-sensitive yeast mutants, fluorescence/electron microscopy, colocalization with Sec7p and COPI\",\n      \"pmids\": [\"16314430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast trafficking step not directly demonstrated for mammalian TRAPPC9\", \"GEF substrate in yeast not identified here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how TRAPPC9 assembles into the mammalian TRAPPII complex, showing TRAPPC2 is the adaptor that bridges TRAPPC9 to TRAPPC10 and that disease mutations disrupt this.\",\n      \"evidence\": \"Co-IP in mammalian cells with wild-type and disease-mutant constructs\",\n      \"pmids\": [\"21858081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; stoichiometry and structure of the assembled complex not determined\", \"Functional consequence of assembly on GEF activity untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected TRAPPC9 to microtubule-based vesicle transport by showing it competes with COPII for p150Glued binding, providing a handoff mechanism from coat to dynactin.\",\n      \"evidence\": \"Co-IP, in vitro binding competition, MTOC localization competition assays\",\n      \"pmids\": [\"22279557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance to physiological transport not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed the NF-\\u03baB/differentiation function operates in a defined neuronal population, mapping TRAPPC9 to cholinergic and nitrergic enteric neurons.\",\n      \"evidence\": \"shRNA/overexpression in enteric neuronal line with NF-\\u03baB reporter; multi-label immunofluorescence in whole-mount intestine\",\n      \"pmids\": [\"24011459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between enteric NF-\\u03baB role and organismal phenotype not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed phosphorylation-dependent, endogenous binding of TRAPPC9 to active IKK2 and extended the NF-\\u03baB role to tumor growth and survival.\",\n      \"evidence\": \"Endogenous co-IP, shRNA knockdown, NF-\\u03baB reporter, xenograft tumor models\",\n      \"pmids\": [\"25704885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic mechanism on IKK2 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Broadened the signaling output by showing TRAPPC9 also modulates TNF\\u03b1-induced MAPK (ERK/JNK) phosphorylation alongside canonical NF-\\u03baB.\",\n      \"evidence\": \"shRNA knockdown in HCT116 cells, pathway western blotting after TNF\\u03b1, orthotopic xenograft\",\n      \"pmids\": [\"28125661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting TRAPPC9 to MAPK branch unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the in vivo GEF function and disease mechanism: TRAPPC9 loss impairs Rab11 activation and endocytic recycling, producing brain growth and cognitive deficits reversible by dopamine receptor manipulation.\",\n      \"evidence\": \"Trappc9 KO mice, Rab11-GTP pull-down, neuronal recycling assay, pharmacological rescue\",\n      \"pmids\": [\"33208359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GEF catalysis on Rab11 not reconstituted biochemically\", \"How recycling defect leads to dopamine receptor imbalance unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the genetics of disease severity, showing maternal-biased imprinted expression creates a dose-threshold whereby maternal allele loss recapitulates the knockout phenotype.\",\n      \"evidence\": \"Allele-specific expression, reciprocal heterozygous and KO mice, MRI, behavior, human case\",\n      \"pmids\": [\"32877400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Imprinting control region/regulatory mechanism not mapped\", \"Conservation of imprinting in humans not fully established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a cytoskeletal partner, showing TRAPPC9 binds L-plastin and organizes actin and podosome formation in osteoclasts.\",\n      \"evidence\": \"Co-IP/mass spectrometry, reciprocal co-IP, immunofluorescence, overexpression in osteoclasts\",\n      \"pmids\": [\"31453638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship of L-plastin binding to TRAPPII GEF function unknown\", \"Single lab, overexpression-based\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked TRAPPC9 deficiency to a congenital disorder of glycosylation, expanding its phenotypic spectrum to a metabolic defect.\",\n      \"evidence\": \"Patient N-glycosylation analysis, tracer metabolomics, wild-type complementation, immunofluorescence in fibroblasts\",\n      \"pmids\": [\"35042660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic route from trafficking defect to glycosylation abnormality not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected TRAPPC9 to stem cell maintenance and lipid/adipogenic homeostasis, showing KO causes premature senescence, lipid droplet accumulation, altered Rab expression and autophagy, and neural stem cell depletion.\",\n      \"evidence\": \"Trappc9 KO ASC differentiation, western blotting of Rab and autophagy markers, neural stem cell immunofluorescence\",\n      \"pmids\": [\"35563289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal ordering of senescence, Rab upregulation and autophagy not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the Rab18-dependent lipid droplet role in neurons, showing TRAPPC9 loss enlarges LDs, reduces Perilipin-2 coating, and depletes hippocampal neural stem cells.\",\n      \"evidence\": \"Trappc9 KO mice, MRI, lipid droplet staining in primary hippocampal neurons, Sox2/Perilipin-2 immunofluorescence\",\n      \"pmids\": [\"38331351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GEF activity toward Rab18 not biochemically reconstituted here\", \"Link between LD defect and stem cell loss correlative\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the neurodevelopmental and metabolic phenotype, showing TRAPPC9 is required for dopamine synapse/release structure formation and that dopamine receptor pharmacology relieves obesity and NAFLD.\",\n      \"evidence\": \"Trappc9 KO mice, RNA-seq of DRD2 neurons, synaptosome proteomics, histology, pharmacological rescue\",\n      \"pmids\": [\"38889014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between trafficking defect and reduced release structures unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated functional exploitation of the TRAPPC9-Rab18 axis by a pathogen, with Leishmania upregulating TRAPPC9/Rab18 via miR-1914-3p suppression to recruit host lipid bodies.\",\n      \"evidence\": \"miRNA over/inhibition, Dicer knockdown, reporter assays, lipid body imaging and fatty acid transfer in macrophages\",\n      \"pmids\": [\"38412149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GEF assay on Rab18 not performed in this context\", \"Generalizability beyond Leishmania infection unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRAPPC9's distinct activities \\u2014 NF-\\u03baB scaffolding, Rab GEF function, and cytoskeletal/dynactin coupling \\u2014 are mechanistically coordinated within or independent of the TRAPPII complex remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted biochemistry confirming TRAPPC9 catalyzes Rab11/Rab18 nucleotide exchange\", \"No structure of the mammalian TRAPPII complex containing TRAPPC9\", \"Whether NF-\\u03baB and trafficking functions use the same molecular surface unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 13, 0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [11, 8]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 6, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"complexes\": [\"TRAPPII complex\"],\n    \"partners\": [\"TRAPPC2\", \"TRAPPC10\", \"NIK\", \"IKBKB\", \"DCTN1\", \"LCP1\", \"RAB11\", \"RAB18\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}