{"gene":"TOM1L2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2023,"finding":"TOM1L2 directly binds K63-linked ubiquitin (UbK63) chains and the BBSome trafficking complex inside cilia, and is required for retrieval of ubiquitinated GPCRs (SSTR3, Smoothened, GPR161) from cilia; targeted disruption of the TOM1L2/BBSome interaction causes accumulation of TOM1L2, ubiquitin, and these GPCRs inside cilia of human and mouse cells.","method":"Co-immunoprecipitation, direct binding assays, genetic disruption of TOM1L2/BBSome interaction, live-cell imaging, loss-of-function in Chlamydomonas ortholog","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, direct binding demonstrated, loss-of-function with specific ciliary GPCR accumulation phenotype, replicated in both mammalian cells and algal ortholog","pmids":["37019113"],"is_preprint":false},{"year":2006,"finding":"The GAT domain of TOM1L2 interacts with Tollip, and the C-terminal region of TOM1L2 interacts with clathrin heavy chain; when co-expressed with Tollip, TOM1L2 recruits clathrin onto endosomes.","method":"Co-immunoprecipitation, GST pulldown, co-expression/colocalization fluorescence microscopy","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and pulldown with colocalization, single lab, replicated across all three TOM1 family members in the same study","pmids":["16412388"],"is_preprint":false},{"year":2006,"finding":"TOM1L2 associates with Src kinase and affects mitogenic signaling induced by platelet-derived growth factor (PDGF), consistent with partial functional redundancy with TOM1L1 in regulating SFK mitogenic signaling.","method":"Co-immunoprecipitation, DNA synthesis assays, overexpression studies","journal":"Molecular and cellular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/OE experiment for TOM1L2 specifically, primary focus of paper is TOM1L1; TOM1L2 data is secondary","pmids":["16479011"],"is_preprint":false},{"year":2017,"finding":"TOM1/TOM1L2 localizes to MYO6-positive peripheral APPL1- and RAB5-positive signaling endosomes at the cell cortex, and depletion of MYO6 disrupts this endosomal localization and reduces AKT phosphorylation and RAC-dependent membrane ruffling.","method":"Immunofluorescence colocalization, siRNA depletion, AKT phosphorylation assay, live-cell imaging","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization tied to functional consequence (AKT signaling), siRNA KD with defined phenotypic readout, single lab with multiple orthogonal methods","pmids":["28591580"],"is_preprint":false},{"year":2020,"finding":"MYO6, GIPC1, and TOM1/L2 form a complex in testis and co-localize to the early APPL1-positive endocytic compartment of tubulobulbar complexes (TBCs) at the Sertoli cell-spermatid interface; loss of MYO6 disrupts spatial organization of TOM1/L2-positive early endosomes and impairs endocytosis during spermiogenesis.","method":"Co-immunoprecipitation, immunofluorescence colocalization, Snell's waltzer MYO6 knockout mouse model, electron microscopy","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP demonstrating complex, KO mouse with specific endosomal phenotype, multiple imaging methods, single lab","pmids":["31901088"],"is_preprint":false},{"year":2020,"finding":"MYO6 together with its binding partner TOM1/L2 is present at/around the spermatid Golgi complex and the nascent acrosome; depletion of MYO6 in Snell's waltzer mice causes structural disruptions of the Golgi complex and affects acrosomal granule positioning, implicating TOM1/L2-MYO6 in Golgi-associated membrane trafficking during acrosome biogenesis.","method":"Immunofluorescence, cytochemical staining, ultrastructural electron microscopy, Snell's waltzer MYO6 KO mouse","journal":"Biology of reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — TOM1/L2 colocalization with MYO6 shown, but mechanistic role of TOM1L2 itself not directly tested; phenotype attributed to MYO6 loss","pmids":["32412041"],"is_preprint":false},{"year":2008,"finding":"Tom1l2-GFP fusion protein co-localizes with Golgi compartments in cells, supporting a role for TOM1L2 in cellular trafficking; Tom1l2 hypomorphic mice exhibit splenomegaly, elevated B- and T-cell counts, impaired humoral response, increased infections and tumors.","method":"GFP fusion protein localization (fluorescence microscopy), gene-trap hypomorphic mouse model, immunological phenotyping","journal":"Mammalian genome","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment plus in vivo loss-of-function with specific immune phenotype, single lab with multiple methods","pmids":["18343975"],"is_preprint":false},{"year":2023,"finding":"TOM1L2 acts as an adaptor protein that recruits Rab41 to damaged xenophagolysosomal membranes; the TOM1L2-Rab41 pathway recruits AAA-ATPase VPS4 to complete ESCRT-mediated membrane repair, and this pathway is critical for efficient clearance of bacteria through xenophagy.","method":"Confocal microscopy, intrabody expression against bacterial cytolysin, Rab GTPase screen, co-localization and recruitment assays, functional xenophagy/bacteria clearance assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct recruitment demonstrated by imaging, functional pathway established by loss-of-function with bacterial clearance readout, single lab with multiple methods","pmids":["37802980"],"is_preprint":false},{"year":2003,"finding":"Endofin does NOT interact with TOM1-like 2 (TOM1-L2) via the C-terminal region used for TOM1 binding; endofin specifically recruits TOM1 but not TOM1-L2 to endosomes.","method":"GST pulldown, co-immunoprecipitation, yeast two-hybrid","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative finding established by multiple binding assays (pulldown + co-IP), clearly distinguishing TOM1L2 from TOM1","pmids":["14613930"],"is_preprint":false},{"year":2017,"finding":"TOM1L2 forms a gene fusion (TOM1L2-BRAF) in myxoinflammatory fibroblastic sarcoma, detected by targeted RNA sequencing, and BRAF rearrangements/amplification were identified as a recurrent genetic alteration in a subset of TGFBR3-MGEA5 fusion-negative MIFS; downstream phospho-ERK was positive in all tested cases.","method":"Targeted RNA sequencing, FISH, immunohistochemistry for phospho-ERK","journal":"The American journal of surgical pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct detection of fusion transcript by RNA-seq with FISH validation in multiple cases; ERK activation confirmed by IHC as functional readout","pmids":["28692601"],"is_preprint":false},{"year":2026,"finding":"Tom1l2-dependent membrane fusion between hUCMSC mitochondrial extracellular vesicles and neuronal mitochondria mediates mitochondrial transfer; this process restores mitochondrial membrane potential and upregulates cardiolipin synthase 1 (CRLS1), preserving inner mitochondrial membrane integrity and stabilizing respiratory chain complexes after ischemia.","method":"In vitro ischemia model, live-cell imaging of mitochondrial fusion, mitochondrial membrane potential assay, Western blot, functional neuronal recovery assays","journal":"Redox biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single paper, mechanistic role of TOM1L2 in membrane fusion inferred from functional outcomes without direct mutagenesis or structural validation","pmids":["41795421"],"is_preprint":false},{"year":2026,"finding":"TOM1 family proteins, including TOM1-L2, function as early adaptors within the ESCRT-0 machinery to recognize ubiquitinated cargo; they interact with ubiquitin and with TOLLIP to facilitate cargo sequestration and endosomal maturation, and also link autophagosomes and endosomes through interaction with myosin VI.","method":"Review/synthesis of experimental findings from prior studies (Co-IP, binding assays, functional trafficking assays)","journal":"Cell communication and signaling : CCS","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper synthesizing prior experimental findings; no new direct experiments on TOM1L2 reported in this paper","pmids":["42192436"],"is_preprint":false}],"current_model":"TOM1L2 is an ancestral ESCRT-0 adaptor protein that recognizes K63-linked ubiquitin chains and engages the BBSome to retrieve ubiquitinated GPCRs from cilia; it also recruits clathrin to endosomes via Tollip, acts as an adaptor linking Rab41 to damaged membranes for ESCRT/VPS4-mediated repair during xenophagy, localizes to APPL1-positive early endosomes via a complex with MYO6 and GIPC1 to support endocytic trafficking and AKT signaling, and participates in immune regulation as demonstrated by the immunological phenotype of Tom1l2 hypomorphic mice."},"narrative":{"mechanistic_narrative":"TOM1L2 is a ubiquitin-recognizing membrane-trafficking adaptor that couples ubiquitinated cargo to clathrin- and ESCRT-associated sorting machinery across endosomal, ciliary, and autophagic compartments [PMID:37019113, PMID:16412388, PMID:37802980]. It directly binds K63-linked ubiquitin chains and the BBSome inside cilia, where it is required to retrieve ubiquitinated GPCRs (SSTR3, Smoothened, GPR161); disrupting the TOM1L2–BBSome interaction traps TOM1L2, ubiquitin, and these receptors in the cilium [PMID:37019113]. At endosomes, its GAT domain binds Tollip while its C-terminus binds clathrin heavy chain, allowing TOM1L2 to recruit clathrin onto endosomal membranes when co-expressed with Tollip [PMID:16412388]. TOM1L2 localizes to MYO6-positive APPL1/RAB5 early signaling endosomes through a complex with MYO6 and GIPC1, and loss of MYO6 disperses these endosomes and reduces AKT phosphorylation and RAC-dependent membrane ruffling, linking the adaptor to growth-factor signaling and to endocytosis during spermiogenesis [PMID:28591580, PMID:31901088]. During xenophagy, TOM1L2 serves as an adaptor that recruits Rab41 to damaged xenophagolysosomal membranes and brings in the AAA-ATPase VPS4 for ESCRT-mediated membrane repair, supporting clearance of intracellular bacteria [PMID:37802980]. In vivo, Tom1l2 hypomorphic mice show splenomegaly, expanded B- and T-cell populations, impaired humoral responses, and increased infection and tumor susceptibility, indicating a physiological role in immune regulation [PMID:18343975].","teleology":[{"year":2006,"claim":"Established the first molecular interactions of TOM1L2 in endosomal sorting, showing it bridges Tollip and clathrin to mark it as a clathrin-recruiting endosomal adaptor.","evidence":"Co-IP, GST pulldown, and co-expression colocalization defining GAT–Tollip and C-terminal–clathrin interactions","pmids":["16412388"],"confidence":"Medium","gaps":["Did not define the ubiquitinated cargo handled at endosomes","Clathrin recruitment shown only on co-overexpression, not endogenous","No structural basis for the GAT–Tollip interface"]},{"year":2006,"claim":"Linked TOM1L2 to receptor tyrosine kinase signaling by associating it with Src and PDGF-induced mitogenesis, hinting at a signaling adaptor role.","evidence":"Co-IP, DNA synthesis assays, and overexpression in a study centered on TOM1L1","pmids":["16479011"],"confidence":"Low","gaps":["TOM1L2 data secondary to TOM1L1, single Co-IP/overexpression experiment","Direct effect of endogenous TOM1L2 on Src signaling untested","No mechanistic connection to endosomal function"]},{"year":2003,"claim":"Distinguished TOM1L2 from the paralog TOM1 by showing endofin recruits TOM1 but not TOM1L2 to endosomes, establishing partner specificity within the family.","evidence":"GST pulldown, co-IP, and yeast two-hybrid demonstrating absent endofin–TOM1L2 binding","pmids":["14613930"],"confidence":"Medium","gaps":["Negative result does not identify TOM1L2's own endosomal recruiter","Does not address functional consequences of the divergence"]},{"year":2008,"claim":"Provided the first in vivo loss-of-function evidence, tying TOM1L2 to Golgi-associated trafficking and immune homeostasis.","evidence":"GFP-fusion Golgi colocalization and gene-trap hypomorphic mouse with immunological phenotyping","pmids":["18343975"],"confidence":"Medium","gaps":["Hypomorph leaves residual function; molecular basis of immune defect undefined","Connection between Golgi localization and the immune phenotype not established"]},{"year":2017,"claim":"Placed TOM1L2 on MYO6-dependent APPL1/RAB5 signaling endosomes and connected it functionally to AKT signaling and membrane ruffling.","evidence":"Immunofluorescence colocalization, siRNA depletion of MYO6, AKT phosphorylation and live-cell imaging readouts","pmids":["28591580"],"confidence":"Medium","gaps":["Direct contribution of TOM1L2 (vs MYO6) to AKT signaling not isolated","Cargo sorted at these endosomes not identified"]},{"year":2020,"claim":"Defined a MYO6–GIPC1–TOM1/L2 complex organizing early endosomes during spermiogenesis, extending the endosomal role to a tissue-specific context.","evidence":"Reciprocal co-IP, immunofluorescence, electron microscopy, and Snell's waltzer MYO6 KO mouse","pmids":["31901088","32412041"],"confidence":"Medium","gaps":["Phenotypes driven by MYO6 loss; TOM1L2's own requirement not directly tested","Golgi/acrosome involvement remains correlative"]},{"year":2023,"claim":"Identified TOM1L2 as a direct K63-ubiquitin and BBSome binder required to retrieve ubiquitinated GPCRs from cilia, defining a conserved ancestral ESCRT-0-like adaptor function.","evidence":"Reciprocal co-IP, direct binding assays, genetic disruption of the TOM1L2–BBSome interface, live imaging, and Chlamydomonas ortholog loss-of-function","pmids":["37019113"],"confidence":"High","gaps":["Structural basis of simultaneous ubiquitin and BBSome engagement unresolved","Whether ciliary retrieval uses the same Tollip/clathrin machinery as endosomes unknown"]},{"year":2023,"claim":"Extended the adaptor role to membrane repair, showing TOM1L2 recruits Rab41 and VPS4 to damaged xenophagolysosomal membranes for ESCRT-mediated repair and bacterial clearance.","evidence":"Confocal imaging, intrabody against bacterial cytolysin, Rab GTPase screen, recruitment and bacterial clearance assays","pmids":["37802980"],"confidence":"Medium","gaps":["Direct TOM1L2–Rab41 binding interface not structurally defined","How damage is sensed to recruit TOM1L2 unknown"]},{"year":2026,"claim":"Implicated TOM1L2 in mitochondrial extracellular-vesicle membrane fusion mediating mitochondrial transfer and metabolic rescue after ischemia.","evidence":"In vitro ischemia model, live imaging of mitochondrial fusion, membrane potential assays, Western blot for CRLS1, and functional recovery assays","pmids":["41795421"],"confidence":"Low","gaps":["TOM1L2 role inferred from functional outcomes without direct mutagenesis or structural validation","Mechanism of TOM1L2-mediated fusion undefined","Single-lab, single-paper observation"]},{"year":null,"claim":"How TOM1L2's distinct cargo-recognition and recruitment activities are partitioned and regulated across cilia, endosomes, autophagolysosomes, and mitochondria-related membranes remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model integrating ubiquitin, BBSome, Tollip, clathrin, and Rab41 binding","Regulatory inputs selecting among compartments are unknown","Substrate spectrum beyond named GPCRs uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,3,4]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[6]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,3,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3]}],"complexes":["BBSome","MYO6-GIPC1-TOM1L2 complex"],"partners":["BBSOME","TOLLIP","CLATHRIN HEAVY CHAIN","MYO6","GIPC1","APPL1","RAB41","VPS4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZVM7","full_name":"TOM1-like protein 2","aliases":["Target of Myb-like protein 2"],"length_aa":507,"mass_kda":55.6,"function":"Acts as a MYO6/Myosin VI adapter protein that targets myosin VI to endocytic structures (PubMed:23023224). May also play a role in recruiting clathrin to endosomes (PubMed:16412388). May regulate growth factor-induced mitogenic signaling (PubMed:16479011)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6ZVM7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TOM1L2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MYO6","stoichiometry":4.0},{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"TOLLIP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TOM1L2","total_profiled":1310},"omim":[{"mim_id":"615519","title":"TARGET OF MYB1-LIKE 2 MEMBRANE TRAFFICKING PROTEIN; TOM1L2","url":"https://www.omim.org/entry/615519"},{"mim_id":"608880","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 16; ZFYVE16","url":"https://www.omim.org/entry/608880"},{"mim_id":"604701","title":"TARGET OF MYB1-LIKE 1 MEMBRANE TRAFFICKING PROTEIN; TOM1L1","url":"https://www.omim.org/entry/604701"},{"mim_id":"604700","title":"TARGET OF MYB1 MEMBRANE TRAFFICKING PROTEIN; TOM1","url":"https://www.omim.org/entry/604700"},{"mim_id":"104300","title":"ALZHEIMER DISEASE, FAMILIAL, 1; AD1","url":"https://www.omim.org/entry/104300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Microtubules","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":132.0}],"url":"https://www.proteinatlas.org/search/TOM1L2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q6ZVM7","domains":[{"cath_id":"1.25.40.90","chopping":"1-156","consensus_level":"high","plddt":94.3369,"start":1,"end":156},{"cath_id":"1.20.58.160","chopping":"217-314","consensus_level":"high","plddt":93.1083,"start":217,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZVM7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZVM7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZVM7-F1-predicted_aligned_error_v6.png","plddt_mean":69.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TOM1L2","jax_strain_url":"https://www.jax.org/strain/search?query=TOM1L2"},"sequence":{"accession":"Q6ZVM7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZVM7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZVM7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZVM7"}},"corpus_meta":[{"pmid":"34381170","id":"PMC_34381170","title":"Identification 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targeted disruption of the TOM1L2/BBSome interaction causes accumulation of TOM1L2, ubiquitin, and these GPCRs inside cilia of human and mouse cells.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays, genetic disruption of TOM1L2/BBSome interaction, live-cell imaging, loss-of-function in Chlamydomonas ortholog\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, direct binding demonstrated, loss-of-function with specific ciliary GPCR accumulation phenotype, replicated in both mammalian cells and algal ortholog\",\n      \"pmids\": [\"37019113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The GAT domain of TOM1L2 interacts with Tollip, and the C-terminal region of TOM1L2 interacts with clathrin heavy chain; when co-expressed with Tollip, TOM1L2 recruits clathrin onto endosomes.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, co-expression/colocalization fluorescence microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and pulldown with colocalization, single lab, replicated across all three TOM1 family members in the same study\",\n      \"pmids\": [\"16412388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TOM1L2 associates with Src kinase and affects mitogenic signaling induced by platelet-derived growth factor (PDGF), consistent with partial functional redundancy with TOM1L1 in regulating SFK mitogenic signaling.\",\n      \"method\": \"Co-immunoprecipitation, DNA synthesis assays, overexpression studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/OE experiment for TOM1L2 specifically, primary focus of paper is TOM1L1; TOM1L2 data is secondary\",\n      \"pmids\": [\"16479011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TOM1/TOM1L2 localizes to MYO6-positive peripheral APPL1- and RAB5-positive signaling endosomes at the cell cortex, and depletion of MYO6 disrupts this endosomal localization and reduces AKT phosphorylation and RAC-dependent membrane ruffling.\",\n      \"method\": \"Immunofluorescence colocalization, siRNA depletion, AKT phosphorylation assay, live-cell imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization tied to functional consequence (AKT signaling), siRNA KD with defined phenotypic readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28591580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYO6, GIPC1, and TOM1/L2 form a complex in testis and co-localize to the early APPL1-positive endocytic compartment of tubulobulbar complexes (TBCs) at the Sertoli cell-spermatid interface; loss of MYO6 disrupts spatial organization of TOM1/L2-positive early endosomes and impairs endocytosis during spermiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, Snell's waltzer MYO6 knockout mouse model, electron microscopy\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP demonstrating complex, KO mouse with specific endosomal phenotype, multiple imaging methods, single lab\",\n      \"pmids\": [\"31901088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYO6 together with its binding partner TOM1/L2 is present at/around the spermatid Golgi complex and the nascent acrosome; depletion of MYO6 in Snell's waltzer mice causes structural disruptions of the Golgi complex and affects acrosomal granule positioning, implicating TOM1/L2-MYO6 in Golgi-associated membrane trafficking during acrosome biogenesis.\",\n      \"method\": \"Immunofluorescence, cytochemical staining, ultrastructural electron microscopy, Snell's waltzer MYO6 KO mouse\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — TOM1/L2 colocalization with MYO6 shown, but mechanistic role of TOM1L2 itself not directly tested; phenotype attributed to MYO6 loss\",\n      \"pmids\": [\"32412041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tom1l2-GFP fusion protein co-localizes with Golgi compartments in cells, supporting a role for TOM1L2 in cellular trafficking; Tom1l2 hypomorphic mice exhibit splenomegaly, elevated B- and T-cell counts, impaired humoral response, increased infections and tumors.\",\n      \"method\": \"GFP fusion protein localization (fluorescence microscopy), gene-trap hypomorphic mouse model, immunological phenotyping\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment plus in vivo loss-of-function with specific immune phenotype, single lab with multiple methods\",\n      \"pmids\": [\"18343975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TOM1L2 acts as an adaptor protein that recruits Rab41 to damaged xenophagolysosomal membranes; the TOM1L2-Rab41 pathway recruits AAA-ATPase VPS4 to complete ESCRT-mediated membrane repair, and this pathway is critical for efficient clearance of bacteria through xenophagy.\",\n      \"method\": \"Confocal microscopy, intrabody expression against bacterial cytolysin, Rab GTPase screen, co-localization and recruitment assays, functional xenophagy/bacteria clearance assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct recruitment demonstrated by imaging, functional pathway established by loss-of-function with bacterial clearance readout, single lab with multiple methods\",\n      \"pmids\": [\"37802980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Endofin does NOT interact with TOM1-like 2 (TOM1-L2) via the C-terminal region used for TOM1 binding; endofin specifically recruits TOM1 but not TOM1-L2 to endosomes.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, yeast two-hybrid\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative finding established by multiple binding assays (pulldown + co-IP), clearly distinguishing TOM1L2 from TOM1\",\n      \"pmids\": [\"14613930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TOM1L2 forms a gene fusion (TOM1L2-BRAF) in myxoinflammatory fibroblastic sarcoma, detected by targeted RNA sequencing, and BRAF rearrangements/amplification were identified as a recurrent genetic alteration in a subset of TGFBR3-MGEA5 fusion-negative MIFS; downstream phospho-ERK was positive in all tested cases.\",\n      \"method\": \"Targeted RNA sequencing, FISH, immunohistochemistry for phospho-ERK\",\n      \"journal\": \"The American journal of surgical pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct detection of fusion transcript by RNA-seq with FISH validation in multiple cases; ERK activation confirmed by IHC as functional readout\",\n      \"pmids\": [\"28692601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Tom1l2-dependent membrane fusion between hUCMSC mitochondrial extracellular vesicles and neuronal mitochondria mediates mitochondrial transfer; this process restores mitochondrial membrane potential and upregulates cardiolipin synthase 1 (CRLS1), preserving inner mitochondrial membrane integrity and stabilizing respiratory chain complexes after ischemia.\",\n      \"method\": \"In vitro ischemia model, live-cell imaging of mitochondrial fusion, mitochondrial membrane potential assay, Western blot, functional neuronal recovery assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single paper, mechanistic role of TOM1L2 in membrane fusion inferred from functional outcomes without direct mutagenesis or structural validation\",\n      \"pmids\": [\"41795421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TOM1 family proteins, including TOM1-L2, function as early adaptors within the ESCRT-0 machinery to recognize ubiquitinated cargo; they interact with ubiquitin and with TOLLIP to facilitate cargo sequestration and endosomal maturation, and also link autophagosomes and endosomes through interaction with myosin VI.\",\n      \"method\": \"Review/synthesis of experimental findings from prior studies (Co-IP, binding assays, functional trafficking assays)\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper synthesizing prior experimental findings; no new direct experiments on TOM1L2 reported in this paper\",\n      \"pmids\": [\"42192436\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TOM1L2 is an ancestral ESCRT-0 adaptor protein that recognizes K63-linked ubiquitin chains and engages the BBSome to retrieve ubiquitinated GPCRs from cilia; it also recruits clathrin to endosomes via Tollip, acts as an adaptor linking Rab41 to damaged membranes for ESCRT/VPS4-mediated repair during xenophagy, localizes to APPL1-positive early endosomes via a complex with MYO6 and GIPC1 to support endocytic trafficking and AKT signaling, and participates in immune regulation as demonstrated by the immunological phenotype of Tom1l2 hypomorphic mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TOM1L2 is a ubiquitin-recognizing membrane-trafficking adaptor that couples ubiquitinated cargo to clathrin- and ESCRT-associated sorting machinery across endosomal, ciliary, and autophagic compartments [#0, #1, #7]. It directly binds K63-linked ubiquitin chains and the BBSome inside cilia, where it is required to retrieve ubiquitinated GPCRs (SSTR3, Smoothened, GPR161); disrupting the TOM1L2–BBSome interaction traps TOM1L2, ubiquitin, and these receptors in the cilium [#0]. At endosomes, its GAT domain binds Tollip while its C-terminus binds clathrin heavy chain, allowing TOM1L2 to recruit clathrin onto endosomal membranes when co-expressed with Tollip [#1]. TOM1L2 localizes to MYO6-positive APPL1/RAB5 early signaling endosomes through a complex with MYO6 and GIPC1, and loss of MYO6 disperses these endosomes and reduces AKT phosphorylation and RAC-dependent membrane ruffling, linking the adaptor to growth-factor signaling and to endocytosis during spermiogenesis [#3, #4]. During xenophagy, TOM1L2 serves as an adaptor that recruits Rab41 to damaged xenophagolysosomal membranes and brings in the AAA-ATPase VPS4 for ESCRT-mediated membrane repair, supporting clearance of intracellular bacteria [#7]. In vivo, Tom1l2 hypomorphic mice show splenomegaly, expanded B- and T-cell populations, impaired humoral responses, and increased infection and tumor susceptibility, indicating a physiological role in immune regulation [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first molecular interactions of TOM1L2 in endosomal sorting, showing it bridges Tollip and clathrin to mark it as a clathrin-recruiting endosomal adaptor.\",\n      \"evidence\": \"Co-IP, GST pulldown, and co-expression colocalization defining GAT–Tollip and C-terminal–clathrin interactions\",\n      \"pmids\": [\"16412388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not define the ubiquitinated cargo handled at endosomes\",\n        \"Clathrin recruitment shown only on co-overexpression, not endogenous\",\n        \"No structural basis for the GAT–Tollip interface\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked TOM1L2 to receptor tyrosine kinase signaling by associating it with Src and PDGF-induced mitogenesis, hinting at a signaling adaptor role.\",\n      \"evidence\": \"Co-IP, DNA synthesis assays, and overexpression in a study centered on TOM1L1\",\n      \"pmids\": [\"16479011\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"TOM1L2 data secondary to TOM1L1, single Co-IP/overexpression experiment\",\n        \"Direct effect of endogenous TOM1L2 on Src signaling untested\",\n        \"No mechanistic connection to endosomal function\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Distinguished TOM1L2 from the paralog TOM1 by showing endofin recruits TOM1 but not TOM1L2 to endosomes, establishing partner specificity within the family.\",\n      \"evidence\": \"GST pulldown, co-IP, and yeast two-hybrid demonstrating absent endofin–TOM1L2 binding\",\n      \"pmids\": [\"14613930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Negative result does not identify TOM1L2's own endosomal recruiter\",\n        \"Does not address functional consequences of the divergence\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided the first in vivo loss-of-function evidence, tying TOM1L2 to Golgi-associated trafficking and immune homeostasis.\",\n      \"evidence\": \"GFP-fusion Golgi colocalization and gene-trap hypomorphic mouse with immunological phenotyping\",\n      \"pmids\": [\"18343975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Hypomorph leaves residual function; molecular basis of immune defect undefined\",\n        \"Connection between Golgi localization and the immune phenotype not established\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed TOM1L2 on MYO6-dependent APPL1/RAB5 signaling endosomes and connected it functionally to AKT signaling and membrane ruffling.\",\n      \"evidence\": \"Immunofluorescence colocalization, siRNA depletion of MYO6, AKT phosphorylation and live-cell imaging readouts\",\n      \"pmids\": [\"28591580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct contribution of TOM1L2 (vs MYO6) to AKT signaling not isolated\",\n        \"Cargo sorted at these endosomes not identified\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a MYO6–GIPC1–TOM1/L2 complex organizing early endosomes during spermiogenesis, extending the endosomal role to a tissue-specific context.\",\n      \"evidence\": \"Reciprocal co-IP, immunofluorescence, electron microscopy, and Snell's waltzer MYO6 KO mouse\",\n      \"pmids\": [\"31901088\", \"32412041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Phenotypes driven by MYO6 loss; TOM1L2's own requirement not directly tested\",\n        \"Golgi/acrosome involvement remains correlative\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified TOM1L2 as a direct K63-ubiquitin and BBSome binder required to retrieve ubiquitinated GPCRs from cilia, defining a conserved ancestral ESCRT-0-like adaptor function.\",\n      \"evidence\": \"Reciprocal co-IP, direct binding assays, genetic disruption of the TOM1L2–BBSome interface, live imaging, and Chlamydomonas ortholog loss-of-function\",\n      \"pmids\": [\"37019113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of simultaneous ubiquitin and BBSome engagement unresolved\",\n        \"Whether ciliary retrieval uses the same Tollip/clathrin machinery as endosomes unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the adaptor role to membrane repair, showing TOM1L2 recruits Rab41 and VPS4 to damaged xenophagolysosomal membranes for ESCRT-mediated repair and bacterial clearance.\",\n      \"evidence\": \"Confocal imaging, intrabody against bacterial cytolysin, Rab GTPase screen, recruitment and bacterial clearance assays\",\n      \"pmids\": [\"37802980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct TOM1L2–Rab41 binding interface not structurally defined\",\n        \"How damage is sensed to recruit TOM1L2 unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated TOM1L2 in mitochondrial extracellular-vesicle membrane fusion mediating mitochondrial transfer and metabolic rescue after ischemia.\",\n      \"evidence\": \"In vitro ischemia model, live imaging of mitochondrial fusion, membrane potential assays, Western blot for CRLS1, and functional recovery assays\",\n      \"pmids\": [\"41795421\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"TOM1L2 role inferred from functional outcomes without direct mutagenesis or structural validation\",\n        \"Mechanism of TOM1L2-mediated fusion undefined\",\n        \"Single-lab, single-paper observation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TOM1L2's distinct cargo-recognition and recruitment activities are partitioned and regulated across cilia, endosomes, autophagolysosomes, and mitochondria-related membranes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model integrating ubiquitin, BBSome, Tollip, clathrin, and Rab41 binding\",\n        \"Regulatory inputs selecting among compartments are unknown\",\n        \"Substrate spectrum beyond named GPCRs uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"BBSome\",\n      \"MYO6-GIPC1-TOM1L2 complex\"\n    ],\n    \"partners\": [\n      \"BBSome\",\n      \"Tollip\",\n      \"clathrin heavy chain\",\n      \"MYO6\",\n      \"GIPC1\",\n      \"APPL1\",\n      \"Rab41\",\n      \"VPS4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}