{"gene":"ARL8A","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2006,"finding":"ARL8A (and its close paralog ARL8B) localizes specifically to lysosomes in mammalian and Drosophila cells. Unlike canonical Arf/Arl proteins, ARL8A/B lack N-terminal myristoylation sites; instead ARL8B is N-terminally acetylated, and an acetylated methionine is necessary for lysosomal localization.","method":"Live cell imaging, subcellular fractionation, biochemical analysis of N-terminal acetylation, site-directed mutagenesis of acetylation site","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional consequence (mutagenesis of acetylation site abrogating localization), replicated in multiple cell systems (mammalian and Drosophila)","pmids":["16537643"],"is_preprint":false},{"year":2006,"finding":"Overexpression of ARL8A or ARL8B causes microtubule-dependent redistribution of lysosomes toward the cell periphery, with live imaging showing increased frequency of lysosome movement both toward and away from the periphery, establishing ARL8A/B as positive regulators of lysosomal transport.","method":"Overexpression in mammalian cells, live cell imaging, microtubule disruption assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — live cell imaging with functional consequence, microtubule dependence confirmed by pharmacological disruption, replicated across cell types","pmids":["16537643"],"is_preprint":false},{"year":2004,"finding":"ARL8A (Gie2) and its homolog Gie1 are required for normal chromosome segregation; expression of dominant-negative mutants in mammalian cells or RNAi knockdown in Drosophila S2 cells causes abnormal chromosome segregation. Gie protein binds tubulin and localizes with microtubules at the spindle mid-zone in late mitosis.","method":"Dominant-negative overexpression in mammalian cells, RNAi knockdown in Drosophila S2 cells, tubulin co-sedimentation/binding assay, immunofluorescence localization","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (RNAi) with defined phenotype and direct tubulin-binding assay, but single lab and tubulin interaction not confirmed by reciprocal Co-IP or structural data","pmids":["15331635"],"is_preprint":false},{"year":2022,"finding":"In the non-infectious cellular context, Arl8a and Arl8b GTPases mediate a kinesin-1 and kinesin-3 (KIF1Bβ) recruitment pathway on lysosomes; the Salmonella effector SifA can establish an analogous kinesin recruitment pathway that functions independently of Arl8a/Arl8b.","method":"Genetic epistasis (infected vs. uninfected cells with Arl8 manipulation), co-immunoprecipitation, loss-of-function (Arl8a/b depletion), fluorescence imaging of lysosomal kinesin recruitment","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiment (Arl8a/b-independent pathway established by absence of Arl8) with Co-IP support, single lab","pmids":["34878110"],"is_preprint":false}],"current_model":"ARL8A is a lysosome-resident Arf-like GTPase that uses N-terminal acetylation (rather than myristoylation) for membrane targeting, acts as a positive regulator of microtubule-dependent lysosomal motility by recruiting kinesin motors (kinesin-1 and kinesin-3), and is also required for proper chromosome segregation through direct tubulin binding and localization to the spindle mid-zone in late mitosis."},"narrative":{"mechanistic_narrative":"ARL8A is an Arf-like GTPase that resides on lysosomes and acts as a positive regulator of microtubule-dependent lysosomal positioning [PMID:16537643]. Distinct from canonical Arf/Arl proteins, ARL8A and its paralog ARL8B lack N-terminal myristoylation and instead rely on N-terminal acetylation for lysosomal membrane targeting [PMID:16537643]. On the lysosomal surface, ARL8A mediates recruitment of plus-end-directed kinesin motors, including kinesin-1 and kinesin-3 (KIF1Bβ), driving lysosome movement toward the cell periphery; overexpression shifts lysosomes peripherally and increases the frequency of bidirectional movement [PMID:16537643, PMID:34878110]. Independent of its lysosomal role, ARL8A (Gie2) binds tubulin directly, localizes to microtubules at the spindle mid-zone in late mitosis, and is required for normal chromosome segregation [PMID:15331635]. Beyond these roles, no further mechanistic detail—including GTPase regulatory cycle, effector structures, or guanine-nucleotide exchange factors—has been characterized in the available corpus.","teleology":[{"year":2004,"claim":"Established the first cellular role for ARL8A by linking it to mitotic fidelity, showing it is not merely a housekeeping GTPase but acts on the mitotic spindle.","evidence":"Dominant-negative overexpression in mammalian cells and RNAi knockdown in Drosophila S2 cells with tubulin co-sedimentation and immunofluorescence","pmids":["15331635"],"confidence":"Medium","gaps":["Tubulin interaction shown by co-sedimentation only, not confirmed by reciprocal Co-IP or structural data","Single lab","Relationship between mitotic role and lysosomal role not resolved"]},{"year":2006,"claim":"Defined ARL8A as a lysosome-resident GTPase using a non-canonical N-terminal acetylation signal for membrane targeting, and as a positive regulator of microtubule-dependent lysosomal motility.","evidence":"Live cell imaging, subcellular fractionation, N-terminal acetylation biochemistry, and acetylation-site mutagenesis in mammalian and Drosophila cells","pmids":["16537643"],"confidence":"High","gaps":["Identity of the motors and adaptors mediating peripheral redistribution not defined at this stage","GTPase cycle and regulators (GEF/GAP) not identified","Mechanism reconciling lysosomal residency with spindle localization not addressed"]},{"year":2022,"claim":"Resolved the motor-recruitment mechanism underlying ARL8A-driven lysosomal motility, showing it recruits kinesin-1 and kinesin-3 (KIF1Bβ) to lysosomes.","evidence":"Genetic epistasis in infected vs. uninfected cells, Arl8a/b depletion, co-immunoprecipitation, and fluorescence imaging of lysosomal kinesin recruitment","pmids":["34878110"],"confidence":"Medium","gaps":["Single lab; Co-IP-based interaction not structurally characterized","Functional contributions of ARL8A versus ARL8B not separated","Adaptor proteins bridging ARL8A to kinesins not detailed in this finding"]},{"year":null,"claim":"How ARL8A coordinates its two distinct roles—lysosomal motor recruitment and mitotic spindle function—and how its GTPase nucleotide cycle is regulated remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No GEF or GAP for ARL8A identified","No structural model of ARL8A-effector or ARL8A-tubulin interactions","Division of labor between ARL8A and ARL8B paralogs uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]}],"complexes":[],"partners":["ARL8B","KIF1B","TUBULIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96BM9","full_name":"ADP-ribosylation factor-like protein 8A","aliases":["ADP-ribosylation factor-like protein 10B","Novel small G protein indispensable for equal chromosome segregation 2"],"length_aa":186,"mass_kda":21.4,"function":"Plays a role in lysosome motility (By similarity). In neurons, mediates the anterograde axonal long-range transport of presynaptic lysosome-related vesicles required for presynaptic biogenesis and synaptic function (By similarity). May play a role in chromosome segregation (By similarity)","subcellular_location":"Late endosome membrane; Lysosome membrane; Cytoplasm, cytoskeleton, spindle; Cell projection, axon; Synapse","url":"https://www.uniprot.org/uniprotkb/Q96BM9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARL8A","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000143862","cell_line_id":"CID000495","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"ARL8B","stoichiometry":10.0},{"gene":"YWHAZ","stoichiometry":0.2},{"gene":"YWHAH","stoichiometry":0.2},{"gene":"YWHAG","stoichiometry":0.2},{"gene":"YWHAE","stoichiometry":0.2},{"gene":"MYO6","stoichiometry":0.2},{"gene":"TRAPPC4","stoichiometry":0.2},{"gene":"BAIAP2","stoichiometry":0.2},{"gene":"GATAD1","stoichiometry":0.2},{"gene":"ARPC1A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000495","total_profiled":1310},"omim":[{"mim_id":"616597","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 8A; ARL8A","url":"https://www.omim.org/entry/616597"},{"mim_id":"616596","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 8B; ARL8B","url":"https://www.omim.org/entry/616596"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":157.0}],"url":"https://www.proteinatlas.org/search/ARL8A"},"hgnc":{"alias_symbol":["FLJ45195","Gie2"],"prev_symbol":["ARL10B"]},"alphafold":{"accession":"Q96BM9","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BM9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BM9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BM9-F1-predicted_aligned_error_v6.png","plddt_mean":92.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARL8A","jax_strain_url":"https://www.jax.org/strain/search?query=ARL8A"},"sequence":{"accession":"Q96BM9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96BM9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96BM9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BM9"}},"corpus_meta":[{"pmid":"16537643","id":"PMC_16537643","title":"An N-terminally acetylated Arf-like GTPase is localised to lysosomes and affects their motility.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16537643","citation_count":188,"is_preprint":false},{"pmid":"15331635","id":"PMC_15331635","title":"Novel small GTPase subfamily capable of associating with tubulin is required for chromosome segregation.","date":"2004","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/15331635","citation_count":42,"is_preprint":false},{"pmid":"30546056","id":"PMC_30546056","title":"Genomic and regulatory characteristics of significant transcription factors in colorectal cancer metastasis.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30546056","citation_count":21,"is_preprint":false},{"pmid":"34298771","id":"PMC_34298771","title":"TBC1D9: An Important Modulator of Tumorigenesis in Breast Cancer.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34298771","citation_count":15,"is_preprint":false},{"pmid":"34878110","id":"PMC_34878110","title":"The Salmonella effector SifA initiates a kinesin-1 and kinesin-3 recruitment process mirroring that mediated by Arl8a and Arl8b.","date":"2022","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34878110","citation_count":7,"is_preprint":false},{"pmid":"41485042","id":"PMC_41485042","title":"Multi-omics and machine learning reveal DPPC as a key contributor to colorectal cancer progression and tumor immune microenvironment remodeling.","date":"2026","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41485042","citation_count":0,"is_preprint":false},{"pmid":"42185984","id":"PMC_42185984","title":"Multi-omics characterization identifies conserved candidate gene and reveals breed-specific regulatory mechanisms underlying growth-related traits in pigs.","date":"2026","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/42185984","citation_count":0,"is_preprint":false},{"pmid":"38161273","id":"PMC_38161273","title":"Using the Bayesian variational spike and slab model in a genome-wide association study for finding associated loci with bipolar disorder.","date":"2023","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38161273","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5896,"output_tokens":1130,"usd":0.017319,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7659,"output_tokens":1797,"usd":0.04161,"stage2_stop_reason":"end_turn"},"total_usd":0.058929,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"ARL8A (and its close paralog ARL8B) localizes specifically to lysosomes in mammalian and Drosophila cells. Unlike canonical Arf/Arl proteins, ARL8A/B lack N-terminal myristoylation sites; instead ARL8B is N-terminally acetylated, and an acetylated methionine is necessary for lysosomal localization.\",\n      \"method\": \"Live cell imaging, subcellular fractionation, biochemical analysis of N-terminal acetylation, site-directed mutagenesis of acetylation site\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional consequence (mutagenesis of acetylation site abrogating localization), replicated in multiple cell systems (mammalian and Drosophila)\",\n      \"pmids\": [\"16537643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpression of ARL8A or ARL8B causes microtubule-dependent redistribution of lysosomes toward the cell periphery, with live imaging showing increased frequency of lysosome movement both toward and away from the periphery, establishing ARL8A/B as positive regulators of lysosomal transport.\",\n      \"method\": \"Overexpression in mammalian cells, live cell imaging, microtubule disruption assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live cell imaging with functional consequence, microtubule dependence confirmed by pharmacological disruption, replicated across cell types\",\n      \"pmids\": [\"16537643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ARL8A (Gie2) and its homolog Gie1 are required for normal chromosome segregation; expression of dominant-negative mutants in mammalian cells or RNAi knockdown in Drosophila S2 cells causes abnormal chromosome segregation. Gie protein binds tubulin and localizes with microtubules at the spindle mid-zone in late mitosis.\",\n      \"method\": \"Dominant-negative overexpression in mammalian cells, RNAi knockdown in Drosophila S2 cells, tubulin co-sedimentation/binding assay, immunofluorescence localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (RNAi) with defined phenotype and direct tubulin-binding assay, but single lab and tubulin interaction not confirmed by reciprocal Co-IP or structural data\",\n      \"pmids\": [\"15331635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In the non-infectious cellular context, Arl8a and Arl8b GTPases mediate a kinesin-1 and kinesin-3 (KIF1Bβ) recruitment pathway on lysosomes; the Salmonella effector SifA can establish an analogous kinesin recruitment pathway that functions independently of Arl8a/Arl8b.\",\n      \"method\": \"Genetic epistasis (infected vs. uninfected cells with Arl8 manipulation), co-immunoprecipitation, loss-of-function (Arl8a/b depletion), fluorescence imaging of lysosomal kinesin recruitment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiment (Arl8a/b-independent pathway established by absence of Arl8) with Co-IP support, single lab\",\n      \"pmids\": [\"34878110\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARL8A is a lysosome-resident Arf-like GTPase that uses N-terminal acetylation (rather than myristoylation) for membrane targeting, acts as a positive regulator of microtubule-dependent lysosomal motility by recruiting kinesin motors (kinesin-1 and kinesin-3), and is also required for proper chromosome segregation through direct tubulin binding and localization to the spindle mid-zone in late mitosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARL8A is an Arf-like GTPase that resides on lysosomes and acts as a positive regulator of microtubule-dependent lysosomal positioning [#0, #1]. Distinct from canonical Arf/Arl proteins, ARL8A and its paralog ARL8B lack N-terminal myristoylation and instead rely on N-terminal acetylation for lysosomal membrane targeting [#0]. On the lysosomal surface, ARL8A mediates recruitment of plus-end-directed kinesin motors, including kinesin-1 and kinesin-3 (KIF1Bβ), driving lysosome movement toward the cell periphery; overexpression shifts lysosomes peripherally and increases the frequency of bidirectional movement [#1, #3]. Independent of its lysosomal role, ARL8A (Gie2) binds tubulin directly, localizes to microtubules at the spindle mid-zone in late mitosis, and is required for normal chromosome segregation [#2]. Beyond these roles, no further mechanistic detail—including GTPase regulatory cycle, effector structures, or guanine-nucleotide exchange factors—has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the first cellular role for ARL8A by linking it to mitotic fidelity, showing it is not merely a housekeeping GTPase but acts on the mitotic spindle.\",\n      \"evidence\": \"Dominant-negative overexpression in mammalian cells and RNAi knockdown in Drosophila S2 cells with tubulin co-sedimentation and immunofluorescence\",\n      \"pmids\": [\"15331635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Tubulin interaction shown by co-sedimentation only, not confirmed by reciprocal Co-IP or structural data\",\n        \"Single lab\",\n        \"Relationship between mitotic role and lysosomal role not resolved\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined ARL8A as a lysosome-resident GTPase using a non-canonical N-terminal acetylation signal for membrane targeting, and as a positive regulator of microtubule-dependent lysosomal motility.\",\n      \"evidence\": \"Live cell imaging, subcellular fractionation, N-terminal acetylation biochemistry, and acetylation-site mutagenesis in mammalian and Drosophila cells\",\n      \"pmids\": [\"16537643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the motors and adaptors mediating peripheral redistribution not defined at this stage\",\n        \"GTPase cycle and regulators (GEF/GAP) not identified\",\n        \"Mechanism reconciling lysosomal residency with spindle localization not addressed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the motor-recruitment mechanism underlying ARL8A-driven lysosomal motility, showing it recruits kinesin-1 and kinesin-3 (KIF1Bβ) to lysosomes.\",\n      \"evidence\": \"Genetic epistasis in infected vs. uninfected cells, Arl8a/b depletion, co-immunoprecipitation, and fluorescence imaging of lysosomal kinesin recruitment\",\n      \"pmids\": [\"34878110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; Co-IP-based interaction not structurally characterized\",\n        \"Functional contributions of ARL8A versus ARL8B not separated\",\n        \"Adaptor proteins bridging ARL8A to kinesins not detailed in this finding\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ARL8A coordinates its two distinct roles—lysosomal motor recruitment and mitotic spindle function—and how its GTPase nucleotide cycle is regulated remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No GEF or GAP for ARL8A identified\",\n        \"No structural model of ARL8A-effector or ARL8A-tubulin interactions\",\n        \"Division of labor between ARL8A and ARL8B paralogs uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ARL8B\", \"KIF1B\", \"tubulin\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}