id: Q96BM9 gene_symbol: ARL8A product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: ARL8A encodes ADP-ribosylation factor-like protein 8A, an ARF-family small GTPase that associates with lysosomal and late-endosomal membranes in its active GTP-bound state. Together with ARL8B, it organizes endolysosome positioning and microtubule-based motility by engaging BORC-dependent recruitment and effectors such as SKIP/PLEKHM2, PLEKHM1/HOPS, and RUFY3/RUFY4. These interactions support peripheral and juxtanuclear redistribution of lysosomes/endolysosomes, cargo delivery to lysosomes, and specialized neuronal axonal transport of lysosome-related vesicles. ARL8A also has reported tubulin/spindle-midzone associations and chromosome-segregation phenotypes from early GIE studies, but those mitotic observations are secondary to its endolysosomal transport role. existing_annotations: - term: id: GO:0005765 label: lysosomal membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: ARL8A lysosomal membrane localization is a core, well-supported location. action: ACCEPT reason: Multiple evidence streams converge on ARL8A/ARL8 proteins as lysosome-associated small GTPases. The original ARL8 study directly showed ARL8A/ARL8B lysosome localization and lysosome motility effects, BORC work places ARL8 recruitment at lysosomal membranes, and lysosomal membrane proteomics is consistent with this localization. additional_reference_ids: - PMID:16537643 - PMID:25898167 supported_by: &id002 - &id006 reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b ... localise to lysosomes in mammalian cells - &id009 reference_id: PMID:25898167 supporting_text: two paralogs of Arl8 (Arl8a and Arl8b) are the only ones known to associate specifically with lysosomes - reference_id: PMID:35314674 supporting_text: ARL8A and ARL8B paralogs ... are unique in their ability to associate with endolysosomes - term: id: GO:0008089 label: anterograde axonal transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Anterograde axonal transport is plausible for ARL8-family endolysosomal transport but is a neuron-specific manifestation of the broader lysosome/endolysosome motility role. action: KEEP_AS_NON_CORE reason: ARL8-dependent endolysosome movement has strong support, including kinesin-linked anterograde movement and neuronal axonal contexts. For human ARL8A in the PN review, however, the core function is lysosome/endolysosome localization and motility; axonal anterograde transport should be retained as a specialized neuronal context rather than the central function. additional_reference_ids: - PMID:35314674 - PMID:25898167 supported_by: - &id003 reference_id: PMID:25898167 supporting_text: This initiates a chain of interactions that promotes the kinesin-dependent movement of lysosomes toward the plus ends of microtubules - &id004 reference_id: PMID:35314674 supporting_text: ARL8 can thus regulate both anterograde and retrograde endolysosome transport through interactions with kinesin and dynein-dynactin motors - &id005 reference_id: PMID:35314674 supporting_text: toward the distal axon in neurons - term: id: GO:0003924 label: GTPase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: GTPase activity is consistent with ARL8A being an ARF-family small GTPase. action: ACCEPT reason: ARL8A is a small GTPase that cycles between GDP-bound and GTP-bound states, and structural/biochemical literature supports nucleotide-bound ARL8 family function. The NAS/IEA evidence is broad but biologically correct for this protein family. additional_reference_ids: - PMID:35314674 supported_by: &id001 - reference_id: PMID:15331635 supporting_text: Here, we identify novel GTPases (human Gie1 and Gie2) that form a distinct subfamily of the small GTPases - reference_id: PMID:35314674 supporting_text: Like other small GTPases, ARL8 cycles between GDP-bound, inactive, and GTP-bound, active forms - term: id: GO:0005525 label: GTP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: GTP binding is consistent with ARL8A being an ARF-family small GTPase. action: ACCEPT reason: ARL8A is a small GTPase that cycles between GDP-bound and GTP-bound states, and structural/biochemical literature supports nucleotide-bound ARL8 family function. The NAS/IEA evidence is broad but biologically correct for this protein family. additional_reference_ids: - PMID:35314674 supported_by: *id001 - term: id: GO:0005765 label: lysosomal membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: ARL8A lysosomal membrane localization is a core, well-supported location. action: ACCEPT reason: Multiple evidence streams converge on ARL8A/ARL8 proteins as lysosome-associated small GTPases. The original ARL8 study directly showed ARL8A/ARL8B lysosome localization and lysosome motility effects, BORC work places ARL8 recruitment at lysosomal membranes, and lysosomal membrane proteomics is consistent with this localization. additional_reference_ids: - PMID:16537643 - PMID:25898167 supported_by: *id002 - term: id: GO:0005819 label: spindle evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: spindle reflects the older GIE/ARL8 mitotic localization study and is not the proteostasis-centered ARL8A role. action: KEEP_AS_NON_CORE reason: The 2004 GIE study supports spindle-midzone/microtubule-associated mitotic localization and chromosome-segregation phenotypes. This appears biologically plausible but is peripheral to the current ARL8A synthesis, where the best-supported function is lysosome/endolysosome localization and motility. additional_reference_ids: - PMID:15331635 supported_by: &id008 - &id012 reference_id: PMID:15331635 supporting_text: Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis - &id013 reference_id: PMID:15331635 supporting_text: Expression of dominant-negative Gie mutants in mammalian cells or knockdown of Gie transcripts using RNA interference in Drosophila S2 cells induced abnormal morphology in the chromosome segregation - term: id: GO:0015031 label: protein transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Generic protein transport is too broad for the ARL8A evidence. action: MODIFY reason: ARL8A regulates lysosome/endolysosome positioning and movement along microtubules rather than protein transport as a generic cargo class. The better process-level assertion is lysosome localization, which captures the positioning/motility role without implying direct protein-cargo transport. proposed_replacement_terms: - id: GO:0032418 label: lysosome localization additional_reference_ids: - PMID:16537643 - PMID:25898167 - PMID:35314674 supported_by: - reference_id: PMID:16537643 supporting_text: Live cell imaging shows that lysosomes move more frequently both toward and away from the cell periphery - *id003 - *id004 - term: id: GO:0030424 label: axon evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: axon is a plausible neuronal context for ARL8-family endolysosomal transport but not the core PN function. action: KEEP_AS_NON_CORE reason: ARL8 family studies support neuronal/axonal endolysosome transport contexts, but ARL8A is principally a lysosomal/late-endosomal small GTPase. These neuron-associated locations should not replace the core lysosomal membrane and late endosome membrane locations. additional_reference_ids: - PMID:35314674 supported_by: &id007 - *id005 - reference_id: PMID:35314674 supporting_text: RUFY3 and RUFY4 promote retrograde transport of ARL8-positive endolysosomal vesicles from the axon to the soma - term: id: GO:0031902 label: late endosome membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Late endosome membrane is a reasonable endolysosomal ARL8A location. action: ACCEPT reason: ARL8A/ARL8B are described as endolysosomal GTPases, with the endolysosome term covering lysosomes, late endosomes, and related organelles. This location is consistent with ARL8 effector studies and UniProt-derived late endosome membrane placement. additional_reference_ids: - PMID:35314674 - PMID:16537643 supported_by: - reference_id: PMID:35314674 supporting_text: endolysosomes broadly to denote various types of lysosomes, late endosomes, and related endolysosomal organelles - *id006 - term: id: GO:0045202 label: synapse evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: synapse is a plausible neuronal context for ARL8-family endolysosomal transport but not the core PN function. action: KEEP_AS_NON_CORE reason: ARL8 family studies support neuronal/axonal endolysosome transport contexts, but ARL8A is principally a lysosomal/late-endosomal small GTPase. These neuron-associated locations should not replace the core lysosomal membrane and late endosome membrane locations. additional_reference_ids: - PMID:35314674 supported_by: *id007 - term: id: GO:0051233 label: spindle midzone evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: spindle midzone reflects the older GIE/ARL8 mitotic localization study and is not the proteostasis-centered ARL8A role. action: KEEP_AS_NON_CORE reason: The 2004 GIE study supports spindle-midzone/microtubule-associated mitotic localization and chromosome-segregation phenotypes. This appears biologically plausible but is peripheral to the current ARL8A synthesis, where the best-supported function is lysosome/endolysosome localization and motility. additional_reference_ids: - PMID:15331635 supported_by: *id008 - term: id: GO:1904115 label: axon cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000108 qualifier: located_in review: summary: axon cytoplasm is a plausible neuronal context for ARL8-family endolysosomal transport but not the core PN function. action: KEEP_AS_NON_CORE reason: ARL8 family studies support neuronal/axonal endolysosome transport contexts, but ARL8A is principally a lysosomal/late-endosomal small GTPase. These neuron-associated locations should not replace the core lysosomal membrane and late endosome membrane locations. additional_reference_ids: - PMID:35314674 supported_by: *id007 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24955142 qualifier: enables review: summary: Protein binding is an uninformative representation of ARL8A interaction data. action: REMOVE reason: GO:0005515 does not describe the specific ARL8A molecular function. Where the interaction is biologically meaningful, it is better captured in the synthesis as GTPase-dependent effector recruitment for lysosome/endolysosome positioning, transport, or HOPS-linked cargo delivery; where the evidence is high-throughput interactomics, it is not sufficient for a functional GO term. supported_by: - reference_id: PMID:24955142 supporting_text: 'Exploration of panviral proteome: high-throughput cloning and functional implications in virus-host interactions.' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Protein binding is an uninformative representation of ARL8A interaction data. action: REMOVE reason: GO:0005515 does not describe the specific ARL8A molecular function. Where the interaction is biologically meaningful, it is better captured in the synthesis as GTPase-dependent effector recruitment for lysosome/endolysosome positioning, transport, or HOPS-linked cargo delivery; where the evidence is high-throughput interactomics, it is not sufficient for a functional GO term. supported_by: - reference_id: PMID:25416956 supporting_text: A proteome-scale map of the human interactome network. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28325809 qualifier: enables review: summary: Protein binding is an uninformative representation of ARL8A interaction data. action: REMOVE reason: GO:0005515 does not describe the specific ARL8A molecular function. Where the interaction is biologically meaningful, it is better captured in the synthesis as GTPase-dependent effector recruitment for lysosome/endolysosome positioning, transport, or HOPS-linked cargo delivery; where the evidence is high-throughput interactomics, it is not sufficient for a functional GO term. supported_by: - reference_id: PMID:28325809 supporting_text: PLEKHM1 directly binds to Arl8b via its N-terminal RUN domain-containing region additional_reference_ids: - PMID:16537643 - PMID:25898167 - PMID:28325809 - PMID:35314674 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Protein binding is an uninformative representation of ARL8A interaction data. action: REMOVE reason: GO:0005515 does not describe the specific ARL8A molecular function. Where the interaction is biologically meaningful, it is better captured in the synthesis as GTPase-dependent effector recruitment for lysosome/endolysosome positioning, transport, or HOPS-linked cargo delivery; where the evidence is high-throughput interactomics, it is not sufficient for a functional GO term. supported_by: - reference_id: PMID:32296183 supporting_text: A reference map of the human binary protein interactome. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Protein binding is an uninformative representation of ARL8A interaction data. action: REMOVE reason: GO:0005515 does not describe the specific ARL8A molecular function. Where the interaction is biologically meaningful, it is better captured in the synthesis as GTPase-dependent effector recruitment for lysosome/endolysosome positioning, transport, or HOPS-linked cargo delivery; where the evidence is high-throughput interactomics, it is not sufficient for a functional GO term. supported_by: - reference_id: PMID:33961781 supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Protein binding is an uninformative representation of ARL8A interaction data. action: REMOVE reason: GO:0005515 does not describe the specific ARL8A molecular function. Where the interaction is biologically meaningful, it is better captured in the synthesis as GTPase-dependent effector recruitment for lysosome/endolysosome positioning, transport, or HOPS-linked cargo delivery; where the evidence is high-throughput interactomics, it is not sufficient for a functional GO term. supported_by: - reference_id: PMID:40205054 supporting_text: Multimodal cell maps as a foundation for structural and functional genomics. - term: id: GO:0008089 label: anterograde axonal transport evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Anterograde axonal transport is plausible for ARL8-family endolysosomal transport but is a neuron-specific manifestation of the broader lysosome/endolysosome motility role. action: KEEP_AS_NON_CORE reason: ARL8-dependent endolysosome movement has strong support, including kinesin-linked anterograde movement and neuronal axonal contexts. For human ARL8A in the PN review, however, the core function is lysosome/endolysosome localization and motility; axonal anterograde transport should be retained as a specialized neuronal context rather than the central function. additional_reference_ids: - PMID:35314674 - PMID:25898167 supported_by: - *id003 - *id004 - *id005 - term: id: GO:0005765 label: lysosomal membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: ARL8A lysosomal membrane localization is a core, well-supported location. action: ACCEPT reason: Multiple evidence streams converge on ARL8A/ARL8 proteins as lysosome-associated small GTPases. The original ARL8 study directly showed ARL8A/ARL8B lysosome localization and lysosome motility effects, BORC work places ARL8 recruitment at lysosomal membranes, and lysosomal membrane proteomics is consistent with this localization. additional_reference_ids: - PMID:16537643 - PMID:25898167 supported_by: *id002 - term: id: GO:0031902 label: late endosome membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Late endosome membrane is a reasonable endolysosomal ARL8A location. action: ACCEPT reason: ARL8A/ARL8B are described as endolysosomal GTPases, with the endolysosome term covering lysosomes, late endosomes, and related organelles. This location is consistent with ARL8 effector studies and UniProt-derived late endosome membrane placement. additional_reference_ids: - PMID:35314674 - PMID:16537643 supported_by: - reference_id: PMID:35314674 supporting_text: endolysosomes broadly to denote various types of lysosomes, late endosomes, and related endolysosomal organelles - *id006 - term: id: GO:0045202 label: synapse evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: synapse is a plausible neuronal context for ARL8-family endolysosomal transport but not the core PN function. action: KEEP_AS_NON_CORE reason: ARL8 family studies support neuronal/axonal endolysosome transport contexts, but ARL8A is principally a lysosomal/late-endosomal small GTPase. These neuron-associated locations should not replace the core lysosomal membrane and late endosome membrane locations. additional_reference_ids: - PMID:35314674 supported_by: *id007 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35314674 qualifier: enables review: summary: Protein binding is an uninformative representation of ARL8A interaction data. action: REMOVE reason: GO:0005515 does not describe the specific ARL8A molecular function. Where the interaction is biologically meaningful, it is better captured in the synthesis as GTPase-dependent effector recruitment for lysosome/endolysosome positioning, transport, or HOPS-linked cargo delivery; where the evidence is high-throughput interactomics, it is not sufficient for a functional GO term. supported_by: - reference_id: PMID:35314674 supporting_text: both RUFY3.1 and RUFY4 have the ability to interact with GTP-bound, but not GDP-bound, ARL8 additional_reference_ids: - PMID:16537643 - PMID:25898167 - PMID:28325809 - PMID:35314674 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25898167 qualifier: enables review: summary: Protein binding is an uninformative representation of ARL8A interaction data. action: REMOVE reason: GO:0005515 does not describe the specific ARL8A molecular function. Where the interaction is biologically meaningful, it is better captured in the synthesis as GTPase-dependent effector recruitment for lysosome/endolysosome positioning, transport, or HOPS-linked cargo delivery; where the evidence is high-throughput interactomics, it is not sufficient for a functional GO term. supported_by: - reference_id: PMID:25898167 supporting_text: BORC functions to recruit Arl8 to lysosomes additional_reference_ids: - PMID:16537643 - PMID:25898167 - PMID:28325809 - PMID:35314674 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798739 qualifier: located_in review: summary: plasma membrane is a Reactome granule-exocytosis context and is not supported as an ARL8A steady-state location. action: REMOVE reason: The Reactome event summaries describe neutrophil granule exocytosis and granule membrane destinations, but they do not provide gene-level evidence that ARL8A localizes to the plasma membrane, azurophil granule membrane, or ficolin-1-rich granule membrane. The experimentally supported ARL8A location is lysosomal/late-endosomal membrane. additional_reference_ids: - PMID:16537643 - PMID:35314674 supported_by: - &id010 reference_id: Reactome:R-HSA-6798739 supporting_text: Azurophil granules undergo limited exocytosis in response to stimulation - *id006 - *id009 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6800426 qualifier: located_in review: summary: plasma membrane is a Reactome granule-exocytosis context and is not supported as an ARL8A steady-state location. action: REMOVE reason: The Reactome event summaries describe neutrophil granule exocytosis and granule membrane destinations, but they do not provide gene-level evidence that ARL8A localizes to the plasma membrane, azurophil granule membrane, or ficolin-1-rich granule membrane. The experimentally supported ARL8A location is lysosomal/late-endosomal membrane. additional_reference_ids: - PMID:16537643 - PMID:35314674 supported_by: - &id011 reference_id: Reactome:R-HSA-6800426 supporting_text: Ficolin-1 rich granules can be differentiated by having low levels of gelatinases and an elevated exocytosis propensity - *id006 - *id009 - term: id: GO:0035577 label: azurophil granule membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798739 qualifier: located_in review: summary: azurophil granule membrane is a Reactome granule-exocytosis context and is not supported as an ARL8A steady-state location. action: REMOVE reason: The Reactome event summaries describe neutrophil granule exocytosis and granule membrane destinations, but they do not provide gene-level evidence that ARL8A localizes to the plasma membrane, azurophil granule membrane, or ficolin-1-rich granule membrane. The experimentally supported ARL8A location is lysosomal/late-endosomal membrane. additional_reference_ids: - PMID:16537643 - PMID:35314674 supported_by: - *id010 - *id006 - *id009 - term: id: GO:0101003 label: ficolin-1-rich granule membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6800426 qualifier: located_in review: summary: ficolin-1-rich granule membrane is a Reactome granule-exocytosis context and is not supported as an ARL8A steady-state location. action: REMOVE reason: The Reactome event summaries describe neutrophil granule exocytosis and granule membrane destinations, but they do not provide gene-level evidence that ARL8A localizes to the plasma membrane, azurophil granule membrane, or ficolin-1-rich granule membrane. The experimentally supported ARL8A location is lysosomal/late-endosomal membrane. additional_reference_ids: - PMID:16537643 - PMID:35314674 supported_by: - *id011 - *id006 - *id009 - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: Membrane is a broad high-throughput location that should be kept only as non-core context. action: KEEP_AS_NON_CORE reason: ARL8A is membrane-associated when active, but the generic membrane term is much less informative than lysosomal membrane and late endosome membrane. The high-throughput NK-cell membrane-proteome result is compatible with membrane association but not a core location term. additional_reference_ids: - PMID:16537643 - PMID:35314674 supported_by: - reference_id: PMID:19946888 supporting_text: Defining the membrane proteome of NK cells. - reference_id: PMID:35314674 supporting_text: the GTP-bound form associates with endolysosomes - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: Extracellular exosome is a high-throughput proteomics context without clear ARL8A functional support. action: MARK_AS_OVER_ANNOTATED reason: The urinary exosome proteomics study is not enough to make extracellular exosome a functional or core ARL8A location. The direct literature instead supports ARL8A at lysosomal and endolysosomal membranes. additional_reference_ids: - PMID:16537643 - PMID:35314674 supported_by: - reference_id: PMID:19056867 supporting_text: Large-scale proteomics and phosphoproteomics of urinary exosomes. - *id006 - *id009 - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 qualifier: located_in review: summary: Lysosomal membrane is supported by lysosomal membrane proteomics and by direct ARL8 lysosome-localization studies. action: ACCEPT reason: The high-throughput lysosomal membrane proteomics call is consistent with independent direct evidence that ARL8A/ARL8B localize to lysosomes and regulate lysosome motility, so this location should be retained as core. additional_reference_ids: - PMID:16537643 - PMID:25898167 supported_by: - reference_id: PMID:17897319 supporting_text: We searched for novel proteins in lysosomal membranes - *id006 - *id009 - term: id: GO:0003924 label: GTPase activity evidence_type: NAS original_reference_id: PMID:15331635 qualifier: enables review: summary: GTPase activity is consistent with ARL8A being an ARF-family small GTPase. action: ACCEPT reason: ARL8A is a small GTPase that cycles between GDP-bound and GTP-bound states, and structural/biochemical literature supports nucleotide-bound ARL8 family function. The NAS/IEA evidence is broad but biologically correct for this protein family. additional_reference_ids: - PMID:35314674 supported_by: *id001 - term: id: GO:0005525 label: GTP binding evidence_type: IDA original_reference_id: PMID:15331635 qualifier: enables review: summary: GTP binding is consistent with ARL8A being an ARF-family small GTPase. action: ACCEPT reason: ARL8A is a small GTPase that cycles between GDP-bound and GTP-bound states, and structural/biochemical literature supports nucleotide-bound ARL8 family function. The NAS/IEA evidence is broad but biologically correct for this protein family. additional_reference_ids: - PMID:35314674 supported_by: *id001 - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:15331635 qualifier: located_in review: summary: Cytoplasm is a broad localization from the original GIE study and is non-core relative to lysosomal/endolysosomal membranes. action: KEEP_AS_NON_CORE reason: ARL8A can have cytosolic and membrane-associated nucleotide states, but cytoplasm is too broad to represent the principal location when lysosomal and late-endosomal membrane terms are available. additional_reference_ids: - PMID:35314674 - PMID:16537643 supported_by: - reference_id: PMID:35314674 supporting_text: Whereas the GDP-bound form is cytosolic, the GTP-bound form associates with endolysosomes - *id006 - term: id: GO:0007059 label: chromosome segregation evidence_type: ISS original_reference_id: PMID:14871887 qualifier: involved_in review: summary: Chromosome segregation is a plausible but non-core mitotic ARL8/GIE role; the original GOA PMID is not the relevant ARL8 paper. action: KEEP_AS_NON_CORE reason: The cited original reference in GOA is a Drosophila Topors paper and does not support ARL8A directly. However, PMID:15331635 does report GIE/ARL8 perturbation effects on chromosome segregation, so the biological idea is not rejected. It should remain non-core for the PN review because lysosome/endolysosome motility is the dominant ARL8A function. additional_reference_ids: - PMID:15331635 supported_by: - reference_id: PMID:14871887 supporting_text: Drosophila Topors is a RING finger-containing protein - *id012 - *id013 - term: id: GO:0030496 label: midbody evidence_type: IDA original_reference_id: PMID:15331635 qualifier: located_in review: summary: midbody reflects the older GIE/ARL8 mitotic localization study and is not the proteostasis-centered ARL8A role. action: KEEP_AS_NON_CORE reason: The 2004 GIE study supports spindle-midzone/microtubule-associated mitotic localization and chromosome-segregation phenotypes. This appears biologically plausible but is peripheral to the current ARL8A synthesis, where the best-supported function is lysosome/endolysosome localization and motility. additional_reference_ids: - PMID:15331635 supported_by: *id008 - term: id: GO:0043014 label: alpha-tubulin binding evidence_type: ISS original_reference_id: PMID:15331635 qualifier: enables review: summary: alpha-tubulin binding is supported by the GIE/ARL8 tubulin-association study but is non-core. action: KEEP_AS_NON_CORE reason: The original ARL8/GIE study reports tubulin binding and spindle-midzone localization. This is a real experimental context, but it does not capture the main ARL8A role in lysosome/endolysosome membrane localization and transport. additional_reference_ids: - PMID:15331635 supported_by: *id008 - term: id: GO:0048487 label: beta-tubulin binding evidence_type: ISS original_reference_id: PMID:15331635 qualifier: enables review: summary: beta-tubulin binding is supported by the GIE/ARL8 tubulin-association study but is non-core. action: KEEP_AS_NON_CORE reason: The original ARL8/GIE study reports tubulin binding and spindle-midzone localization. This is a real experimental context, but it does not capture the main ARL8A role in lysosome/endolysosome membrane localization and transport. additional_reference_ids: - PMID:15331635 supported_by: *id008 - term: id: GO:0051233 label: spindle midzone evidence_type: IDA original_reference_id: PMID:15331635 qualifier: located_in review: summary: spindle midzone reflects the older GIE/ARL8 mitotic localization study and is not the proteostasis-centered ARL8A role. action: KEEP_AS_NON_CORE reason: The 2004 GIE study supports spindle-midzone/microtubule-associated mitotic localization and chromosome-segregation phenotypes. This appears biologically plausible but is peripheral to the current ARL8A synthesis, where the best-supported function is lysosome/endolysosome localization and motility. additional_reference_ids: - PMID:15331635 supported_by: *id008 references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000108 title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:14871887 title: Drosophila Topors is a RING finger-containing protein that functions as a ubiquitin-protein isopeptide ligase for the hairy basic helix-loop-helix repressor protein. findings: [] - id: PMID:15331635 title: Novel small GTPase subfamily capable of associating with tubulin is required for chromosome segregation. findings: [] - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. findings: [] - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: [] - id: PMID:19946888 title: Defining the membrane proteome of NK cells. findings: [] - id: PMID:24955142 title: 'Exploration of panviral proteome: high-throughput cloning and functional implications in virus-host interactions.' findings: [] - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] - id: PMID:25898167 title: BORC, a multisubunit complex that regulates lysosome positioning. findings: [] - id: PMID:28325809 title: The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traffic to lysosomes. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35314674 title: RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin. findings: [] - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: PMID:27851960 title: BORC Functions Upstream of Kinesins 1 and 3 to Coordinate Regional Movement of Lysosomes along Different Microtubule Tracks. full_text_unavailable: true findings: - statement: BORC and ARL8 act upstream of both kinesin-1 (KIF5B) and kinesin-3 (KIF1A/KIF1Bbeta), which move lysosomes on distinct microtubule tracks (KIF5B on central acetylated tubulin, KIF1A/KIF1Bbeta on peripheral tyrosinated tubulin); in an ARL8B-knockout background, siRNA against ARL8A removes the residual ability of kinesin constructs to disperse lysosomes, indicating ARL8A itself contributes to BORC-dependent anterograde lysosome transport. - id: PMID:35653304 title: BORC-ARL8-HOPS ensemble is required for lysosomal cholesterol egress through NPC2. full_text_unavailable: true findings: - statement: The BORC-ARL8-HOPS ensemble is required for egress of free cholesterol from lysosomes; depletion of BORC, ARL8, or HOPS causes lysosomal free-cholesterol accumulation, decreased NPC2 association with lysosomes with increased NPC2 secretion, and increased lysosomal degradation of the CI-mannose-6-phosphate receptor. - id: PMID:37213076 title: Inhibition of endolysosome fusion increases exosome secretion. full_text_unavailable: true findings: - statement: Impairing the BORC-ARL8-HOPS pathway blocks fusion of multivesicular endosomes with lysosomes and increases exosome secretion; the study used HeLa ARL8A/ARL8B double-knockout cells, indicating an ARL8-family requirement for endolysosome fusion that determines exosome output. - id: PMID:38296963 title: DENND6A links Arl8b to a Rab34/RILP/dynein complex, regulating lysosomal positioning and autophagy. full_text_unavailable: true findings: - statement: DENND6A is an ARL8B effector and GEF that activates Rab34 to recruit a RILP/dynein-dynactin complex, driving retrograde (juxtanuclear) lysosome transport and supporting autophagic flux; double knockdown of ARL8A and ARL8B reduces DENND6A-dependent phenotypes, consistent with an ARL8-family contribution. - id: PMID:38128568 title: Biallelic BORCS8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics. full_text_unavailable: true findings: - statement: Biallelic loss-of-function variants in the BORC subunit BORCS8 (which acts upstream of ARL8 to recruit kinesin motors for anterograde lysosome transport) cause a severe early-infantile neurodegenerative disorder in five children; patient alleles impair BORC assembly and peripheral lysosome distribution, validating the BORC-ARL8-kinesin axis physiologically in humans. - id: PMID:39217195 title: Altered expression of vesicular trafficking machinery in prostate cancer affects lysosomal dynamics and provides insight into the underlying biology and disease progression. full_text_unavailable: true findings: - statement: In prostate cancer cohorts, altered expression of lysosomal trafficking machinery including ARL8A was examined; ARL8A expression showed only a non-significant association with overall survival (log-rank P=0.1471, HR 1.927, 95% CI 0.6692-5.547). - id: Reactome:R-HSA-6798739 title: Exocytosis of azurophil granule membrane proteins findings: [] - id: Reactome:R-HSA-6800426 title: Exocytosis of ficolin-rich granule membrane proteins findings: [] - id: PMID:16537643 title: An N-terminally acetylated Arf-like GTPase is localised to lysosomes and affects their motility. findings: [] - id: file:human/ARL8A/ARL8A-uniprot.txt title: UniProtKB record for human ARL8A findings: [] - id: file:human/ARL8A/ARL8A-notes.md title: ARL8A PN-context review notes findings: [] - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_new_to_goa.tsv title: PN projected new-to-GOA annotations report findings: [] - id: file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv title: PN mapping scrutiny report findings: [] core_functions: - description: ARL8A is a lysosomal/late-endosomal small GTPase that regulates endolysosome positioning and microtubule-based motility through BORC-dependent membrane recruitment and GTP-dependent effector interactions. This core activity supports lysosome localization, endolysosomal cargo delivery to lysosomes, and lysosome-related vesicle transport in specialized cellular contexts. molecular_function: id: GO:0003924 label: GTPase activity directly_involved_in: - id: GO:0032418 label: lysosome localization locations: - id: GO:0005765 label: lysosomal membrane - id: GO:0031902 label: late endosome membrane supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b ... localise to lysosomes in mammalian cells - reference_id: PMID:16537643 supporting_text: Overexpression of Arl8a or Arl8b results in a microtubule-dependent redistribution of lysosomes towards the cell periphery - reference_id: PMID:25898167 supporting_text: BORC associates peripherally with the lysosomal membrane, where it functions to recruit the small GTPase Arl8 - reference_id: PMID:28325809 supporting_text: Arl8b binding to PLEKHM1 is required for its function in delivery and, therefore, degradation of endocytic and autophagic cargo in lysosomes - reference_id: PMID:35314674 supporting_text: RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin proposed_new_terms: [] suggested_questions: - question: Should ARL8A receive a direct GO:0061906 autophagosome localization annotation, or should the PN projection remain limited to lysosome/endolysosome positioning until ARL8A-dependent autophagosome movement is shown directly? experts: - GO autophagy editors - GO proteostasis PN curators - question: Should broad ARL8A protein binding annotations be replaced by a more specific curator model of small-GTPase effector recruitment for lysosome/endolysosome transport? experts: - GO molecular function editors - UniProt curators - question: Does ARL8A contribute non-redundantly to BORC-ARL8-HOPS-dependent lysosomal cholesterol egress (NPC2 trafficking) and to endolysosome fusion that limits exosome secretion, or are these roles fully covered by ARL8B in cells expressing both paralogs? experts: - GO lysosome/membrane trafficking curators - lysosomal lipid trafficking experts suggested_experiments: - experiment_type: ARL8A-specific autophagosome positioning assay hypothesis: ARL8A regulates lysosome/endolysosome positioning but does not directly position autophagosomes independently of ARL8B or lysosome movement. description: Use ARL8A knockout, ARL8B knockout, double knockout, and matched rescue cells expressing endogenous-level ARL8A to image LC3-positive autophagosomes and LAMP1-positive lysosomes during basal and induced autophagy. Quantify autophagosome movement, lysosome movement, autophagosome-lysosome contacts, and cargo degradation to separate direct autophagosome localization from lysosome positioning effects. - experiment_type: Effector-binding separation of function hypothesis: ARL8A effector binding to PLEKHM1/HOPS, SKIP, and RUFY3/RUFY4 separates lysosome localization, anterograde movement, retrograde movement, and autophagic cargo-delivery phenotypes. description: Compare wild-type ARL8A and effector-binding-defective mutants in ARL8A/ARL8B-deficient cells, measuring BORC-dependent lysosome recruitment, RUFY3/RUFY4-dependent dynein-dynactin coupling, SKIP/kinesin-dependent peripheral movement, and PLEKHM1/HOPS-dependent delivery of endocytic and autophagic cargo to lysosomes. - experiment_type: ARL8A-specific cholesterol egress and exosome secretion assay hypothesis: ARL8A contributes to BORC-ARL8-HOPS-dependent lysosomal cholesterol egress and to endolysosome fusion that restrains exosome secretion, with partial redundancy with ARL8B. description: Using ARL8A single-knockout, ARL8B single-knockout, double-knockout, and matched rescue HeLa cells, quantify lysosomal free-cholesterol accumulation (filipin), NPC2 lysosomal association versus secretion, and exosome output (CD63/CD9 nanoparticle tracking and immunoblot), to determine the non-redundant contribution of ARL8A to the BORC-ARL8-HOPS cholesterol-egress and endolysosome-fusion programs.