id: Q9NVJ2 gene_symbol: ARL8B product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: ARL8B is a conserved Arf-like small GTPase that associates with lysosomal and endolysosomal membranes in its active GTP-bound state. Through effector interactions with BORC, PLEKHM2/SKIP-kinesin, PLEKHM1/HOPS, VPS41, and RUFY proteins, it coordinates lysosome positioning, endolysosomal cargo delivery, and lysosome fusion or exocytosis in contexts including autophagic cargo degradation, phagosome maturation, antigen presentation, cytolytic granule polarization, plasma membrane repair, and beta-coronavirus egress. alternative_products: - name: '1' id: Q9NVJ2-1 - name: '2' id: Q9NVJ2-2 sequence_note: VSP_056238 existing_annotations: - term: id: GO:0005765 label: lysosomal membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: lysosomal membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - 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 supported mainly by conserved neuronal ARL8 biology and automated/by-similarity transfer. action: KEEP_AS_NON_CORE reason: The annotation is plausible for neuronal endolysosomal or presynaptic-vesicle trafficking, but human ARL8B direct evidence in this review is stronger for general lysosome positioning and cargo delivery. supported_by: - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0003924 label: GTPase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: ARL8B is a small Arf-like GTPase; the GTPase activity annotation is consistent with direct biochemical and sequence evidence. action: ACCEPT reason: GTP binding/hydrolysis and small G-protein switching are core molecular features of ARL8B that underlie effector recruitment on endolysosomal membranes. supported_by: - 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:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - term: id: GO:0003925 label: G protein activity evidence_type: IEA original_reference_id: GO_REF:0000003 qualifier: enables review: summary: ARL8B is a monomeric Arf-like small GTPase, so the heterotrimeric G protein activity term is not the best molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited evidence supports small-GTPase biology captured by GO:0003924 GTPase activity, which is already present and accepted; GO:0003925 is over-broad or semantically imprecise for ARL8B. supported_by: - 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:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - term: id: GO:0005525 label: GTP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: ARL8B is a small Arf-like GTPase; the GTP binding annotation is consistent with direct biochemical and sequence evidence. action: ACCEPT reason: GTP binding/hydrolysis and small G-protein switching are core molecular features of ARL8B that underlie effector recruitment on endolysosomal membranes. supported_by: - 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:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - term: id: GO:0005765 label: lysosomal membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: lysosomal membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0005819 label: spindle evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: spindle comes from the early GIE/ARL8B microtubule and mitosis study. action: KEEP_AS_NON_CORE reason: This appears experimentally supported but peripheral to the dominant lysosomal small-GTPase role established by later work. supported_by: - 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. - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Cytosol is a generic automated localization and is less informative than ARL8B lysosomal membrane/endolysosomal localization. action: MARK_AS_OVER_ANNOTATED reason: ARL8B cycles between soluble and membrane-associated states, but the curated functional signal is the active lysosomal/endolysosomal membrane pool; generic cytosol is over-annotated for this review. supported_by: - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Small GTPase which cycles between active GTP-bound and inactive GDP-bound states - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes - term: id: GO:0015031 label: protein transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: The broad protein transport IEA captures the general trafficking theme but is too nonspecific for ARL8B. action: MARK_AS_OVER_ANNOTATED reason: ARL8B evidence supports lysosome positioning and specific late-endosome/phagosome/autophagosome-to-lysosome traffic rather than generic protein transport; the more specific lysosome localization and late endosome-to-lysosome transport annotations are already present and accepted. supported_by: - reference_id: PMID:21802320 supporting_text: Arl8b silencing resulted in a delay in delivery of fluid phase dextran, receptor-internalized low-density lipoprotein (LDL), and CD1 cargo to lysosomes. - reference_id: PMID:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:28325809 supporting_text: Arl8b, along with its effectors, orchestrates lysosomal transport and fusion. - term: id: GO:0030424 label: axon evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: axon is supported mainly by conserved neuronal ARL8 biology and automated/by-similarity transfer. action: KEEP_AS_NON_CORE reason: The annotation is plausible for neuronal endolysosomal or presynaptic-vesicle trafficking, but human ARL8B direct evidence in this review is stronger for general lysosome positioning and cargo delivery. supported_by: - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0031901 label: early endosome membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: early endosome membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:36282215 supporting_text: Arl8b determines RUFY1 endosomal localization through regulating its interaction with Rab14. - reference_id: PMID:36282215 supporting_text: RUFY1 depletion led to a delay in CI-M6PR retrieval from endosomes to the TGN, resulting in impaired delivery of newly synthesized hydrolases to lysosomes. - 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 core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0045202 label: synapse evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: synapse is supported mainly by conserved neuronal ARL8 biology and automated/by-similarity transfer. action: KEEP_AS_NON_CORE reason: The annotation is plausible for neuronal endolysosomal or presynaptic-vesicle trafficking, but human ARL8B direct evidence in this review is stronger for general lysosome positioning and cargo delivery. supported_by: - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0051233 label: spindle midzone evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: spindle midzone comes from the early GIE/ARL8B microtubule and mitosis study. action: KEEP_AS_NON_CORE reason: This appears experimentally supported but peripheral to the dominant lysosomal small-GTPase role established by later work. supported_by: - 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. - term: id: GO:0101004 label: cytolytic granule membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: cytolytic granule membrane is supported for NK cells, where ARL8B localizes to lytic granules and promotes polarization toward the immune synapse. action: KEEP_AS_NON_CORE reason: This is a well-supported lysosome-related organelle function in a specialized immune-cell context, not the general core function of ARL8B. supported_by: - reference_id: PMID:24088571 supporting_text: Arl8b colocalizes with perforin, granzyme B, and LAMP-1, markers of lytic granules. - term: id: GO:1904115 label: axon cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000108 qualifier: located_in review: summary: axon cytoplasm is supported mainly by conserved neuronal ARL8 biology and automated/by-similarity transfer. action: KEEP_AS_NON_CORE reason: The annotation is plausible for neuronal endolysosomal or presynaptic-vesicle trafficking, but human ARL8B direct evidence in this review is stronger for general lysosome positioning and cargo delivery. supported_by: - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28325809 qualifier: enables review: summary: PLEKHM1 binding is real and biologically important for HOPS-linked lysosomal fusion, but generic protein binding is not an informative GO molecular function for ARL8B. action: MARK_AS_OVER_ANNOTATED reason: ARL8B functions as a regulated small GTPase that recruits specific effectors to endolysosomal membranes; a generic protein binding annotation obscures that biology and is therefore over-annotated. supported_by: - reference_id: PMID:28325809 supporting_text: Arl8b mediates recruitment of HOPS complex to PLEKHM1-positive vesicle contact sites. - reference_id: PMID:28325809 supporting_text: Arl8b binding is crucial for PLEKHM1 to promote lysosomal degradation of endocytic and autophagic cargo. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: The HuRI protein interaction is a broad interactome finding and does not define a specific ARL8B molecular function beyond generic binding. action: MARK_AS_OVER_ANNOTATED reason: ARL8B functions as a regulated small GTPase that recruits specific effectors to endolysosomal membranes; a generic protein binding annotation obscures that biology and is therefore over-annotated. supported_by: - reference_id: PMID:32296183 supporting_text: A reference map of the human binary protein interactome. - term: id: GO:0002505 label: antigen processing and presentation of polysaccharide antigen via MHC class II evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: antigen processing and presentation of polysaccharide antigen via MHC class II is supported by immune-cell lysosomal trafficking studies but is context-specific. action: KEEP_AS_NON_CORE reason: ARL8B controls delivery of antigen-containing cargo to lysosomal compartments; antigen presentation is a downstream immune-cell outcome rather than the core molecular role. supported_by: - reference_id: PMID:21802320 supporting_text: Arl8b silencing resulted in a delay in delivery of fluid phase dextran, receptor-internalized low-density lipoprotein (LDL), and CD1 cargo to lysosomes. - term: id: GO:0005764 label: lysosome evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: lysosome is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - 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 supported mainly by conserved neuronal ARL8 biology and automated/by-similarity transfer. action: KEEP_AS_NON_CORE reason: The annotation is plausible for neuronal endolysosomal or presynaptic-vesicle trafficking, but human ARL8B direct evidence in this review is stronger for general lysosome positioning and cargo delivery. supported_by: - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0046754 label: viral exocytosis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: ARL8B-dependent lysosomal exocytosis is exploited by beta-coronaviruses for viral egress. action: KEEP_AS_NON_CORE reason: The process annotation is supported for infection biology, but it represents pathogen exploitation of ARL8B-dependent lysosomal exocytosis rather than a core host function. supported_by: - reference_id: PMID:33157038 supporting_text: these viruses use a lysosomal, Arl8b-dependent exocytic pathway for release into the extracellular environment. - term: id: GO:1902774 label: late endosome to lysosome transport evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: late endosome to lysosome transport is supported by ARL8B loss-of-function cargo-delivery assays and HOPS recruitment evidence. action: ACCEPT reason: This captures ARL8B-dependent delivery of endocytic cargo to lysosomes, a core part of its endolysosomal trafficking role. supported_by: - reference_id: PMID:21802320 supporting_text: Arl8b silencing resulted in a delay in delivery of fluid phase dextran, receptor-internalized low-density lipoprotein (LDL), and CD1 cargo to lysosomes. - reference_id: PMID:21802320 supporting_text: Arl8b was found to bind and recruit the VPS41 subunit of the HOPS (homotypic fusion and protein sorting) complex to lysosomes. - reference_id: PMID:28325809 supporting_text: Arl8b, along with its effectors, orchestrates lysosomal transport and fusion. - term: id: GO:0005765 label: lysosomal membrane evidence_type: EXP original_reference_id: PMID:16650381 qualifier: located_in review: summary: lysosomal membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0005765 label: lysosomal membrane evidence_type: EXP original_reference_id: PMID:21802320 qualifier: located_in review: summary: lysosomal membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0005765 label: lysosomal membrane evidence_type: EXP original_reference_id: PMID:28325809 qualifier: located_in review: summary: lysosomal membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0005765 label: lysosomal membrane evidence_type: EXP original_reference_id: PMID:29592961 qualifier: located_in review: summary: lysosomal membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0031902 label: late endosome membrane evidence_type: EXP original_reference_id: PMID:16537643 qualifier: located_in review: summary: late endosome membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0045202 label: synapse evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: synapse is supported mainly by conserved neuronal ARL8 biology and automated/by-similarity transfer. action: KEEP_AS_NON_CORE reason: The annotation is plausible for neuronal endolysosomal or presynaptic-vesicle trafficking, but human ARL8B direct evidence in this review is stronger for general lysosome positioning and cargo delivery. supported_by: - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35314674 qualifier: enables review: summary: RUFY3/RUFY4 interactions support ARL8B-dependent endolysosome motor coupling, but generic protein binding does not capture the specific small-GTPase effector relationship. action: MARK_AS_OVER_ANNOTATED reason: ARL8B functions as a regulated small GTPase that recruits specific effectors to endolysosomal membranes; a generic protein binding annotation obscures that biology and is therefore over-annotated. supported_by: - reference_id: PMID:35314674 supporting_text: RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin - reference_id: PMID:35314674 supporting_text: ARL8 can thus regulate both anterograde and retrograde endolysosome transport through interactions with kinesin and dynein-dynactin motors - term: id: GO:0003924 label: GTPase activity evidence_type: IDA original_reference_id: PMID:16537643 qualifier: enables review: summary: ARL8B is a small Arf-like GTPase; the GTPase activity annotation is consistent with direct biochemical and sequence evidence. action: ACCEPT reason: GTP binding/hydrolysis and small G-protein switching are core molecular features of ARL8B that underlie effector recruitment on endolysosomal membranes. supported_by: - 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:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - term: id: GO:0031901 label: early endosome membrane evidence_type: IDA original_reference_id: PMID:36282215 qualifier: is_active_in review: summary: early endosome membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:36282215 supporting_text: Arl8b determines RUFY1 endosomal localization through regulating its interaction with Rab14. - reference_id: PMID:36282215 supporting_text: RUFY1 depletion led to a delay in CI-M6PR retrieval from endosomes to the TGN, resulting in impaired delivery of newly synthesized hydrolases to lysosomes. - term: id: GO:0034498 label: early endosome to Golgi transport evidence_type: IDA original_reference_id: PMID:36282215 qualifier: involved_in review: summary: early endosome to Golgi transport is supported by RUFY1-dependent CI-M6PR retrieval work. action: KEEP_AS_NON_CORE reason: This is a specific cargo-sorting branch of ARL8B biology and supports lysosomal hydrolase delivery, but it is secondary to the major lysosome positioning/fusion role. supported_by: - reference_id: PMID:36282215 supporting_text: RUFY1 depletion led to a delay in CI-M6PR retrieval from endosomes to the TGN, resulting in impaired delivery of newly synthesized hydrolases to lysosomes. - term: id: GO:1902946 label: protein localization to early endosome evidence_type: IDA original_reference_id: PMID:36282215 qualifier: involved_in review: summary: protein localization to early endosome is supported by RUFY1-dependent CI-M6PR retrieval work. action: KEEP_AS_NON_CORE reason: This is a specific cargo-sorting branch of ARL8B biology and supports lysosomal hydrolase delivery, but it is secondary to the major lysosome positioning/fusion role. supported_by: - reference_id: PMID:36282215 supporting_text: Arl8b determines RUFY1 endosomal localization through regulating its interaction with Rab14. - term: id: GO:0046754 label: viral exocytosis evidence_type: IMP original_reference_id: PMID:33157038 qualifier: involved_in review: summary: ARL8B-dependent lysosomal exocytosis is exploited by beta-coronaviruses for viral egress. action: KEEP_AS_NON_CORE reason: The process annotation is supported for infection biology, but it represents pathogen exploitation of ARL8B-dependent lysosomal exocytosis rather than a core host function. supported_by: - reference_id: PMID:33157038 supporting_text: these viruses use a lysosomal, Arl8b-dependent exocytic pathway for release into the extracellular environment. - term: id: GO:0003925 label: G protein activity evidence_type: IDA original_reference_id: PMID:16537643 qualifier: enables review: summary: ARL8B is a monomeric Arf-like small GTPase, so the heterotrimeric G protein activity term is not the best molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The cited evidence supports small-GTPase biology captured by GO:0003924 GTPase activity, which is already present and accepted; GO:0003925 is over-broad or semantically imprecise for ARL8B. supported_by: - 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:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:27808481 qualifier: is_active_in review: summary: lysosomal membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0032418 label: lysosome localization evidence_type: IDA original_reference_id: PMID:16537643 qualifier: involved_in review: summary: Lysosome localization is the best-supported core biological process for ARL8B. action: ACCEPT reason: Multiple independent studies show ARL8B-dependent peripheral/anterograde lysosome positioning through BORC, SKIP/kinesin, and regulation by RNF167. supported_by: - 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:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:25898167 supporting_text: BORC acts at an early stage, recruiting Arl8b to the lysosomal membrane and therefore enabling coupling to the SKIP-Kinesin-1 complex - term: id: GO:0032418 label: lysosome localization evidence_type: IDA original_reference_id: PMID:27808481 qualifier: involved_in review: summary: Lysosome localization is the best-supported core biological process for ARL8B. action: ACCEPT reason: Multiple independent studies show ARL8B-dependent peripheral/anterograde lysosome positioning through BORC, SKIP/kinesin, and regulation by RNF167. supported_by: - 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:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:25898167 supporting_text: BORC acts at an early stage, recruiting Arl8b to the lysosomal membrane and therefore enabling coupling to the SKIP-Kinesin-1 complex - term: id: GO:0042267 label: natural killer cell mediated cytotoxicity evidence_type: IMP original_reference_id: PMID:24088571 qualifier: involved_in review: summary: natural killer cell mediated cytotoxicity is supported for NK cells, where ARL8B localizes to lytic granules and promotes polarization toward the immune synapse. action: KEEP_AS_NON_CORE reason: This is a well-supported lysosome-related organelle function in a specialized immune-cell context, not the general core function of ARL8B. supported_by: - reference_id: PMID:24088571 supporting_text: Arl8b drives the polarization of lytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse - term: id: GO:0101004 label: cytolytic granule membrane evidence_type: IDA original_reference_id: PMID:24088571 qualifier: located_in review: summary: cytolytic granule membrane is supported for NK cells, where ARL8B localizes to lytic granules and promotes polarization toward the immune synapse. action: KEEP_AS_NON_CORE reason: This is a well-supported lysosome-related organelle function in a specialized immune-cell context, not the general core function of ARL8B. supported_by: - reference_id: PMID:24088571 supporting_text: Arl8b colocalizes with perforin, granzyme B, and LAMP-1, markers of lytic granules. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22172677 qualifier: enables review: summary: PLEKHM2/SKIP binding is central to ARL8B-dependent kinesin recruitment, but protein binding is too generic relative to the lysosome localization process annotation. action: MARK_AS_OVER_ANNOTATED reason: ARL8B functions as a regulated small GTPase that recruits specific effectors to endolysosomal membranes; a generic protein binding annotation obscures that biology and is therefore over-annotated. supported_by: - reference_id: PMID:22172677 supporting_text: Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:22172677 qualifier: located_in review: summary: lysosomal membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0032418 label: lysosome localization evidence_type: IMP original_reference_id: PMID:22172677 qualifier: involved_in review: summary: Lysosome localization is the best-supported core biological process for ARL8B. action: ACCEPT reason: Multiple independent studies show ARL8B-dependent peripheral/anterograde lysosome positioning through BORC, SKIP/kinesin, and regulation by RNF167. supported_by: - 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:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:25898167 supporting_text: BORC acts at an early stage, recruiting Arl8b to the lysosomal membrane and therefore enabling coupling to the SKIP-Kinesin-1 complex - term: id: GO:0005764 label: lysosome evidence_type: IDA original_reference_id: PMID:28325809 qualifier: located_in review: summary: lysosome is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0032418 label: lysosome localization evidence_type: IDA original_reference_id: PMID:28325809 qualifier: involved_in review: summary: Lysosome localization is the best-supported core biological process for ARL8B. action: ACCEPT reason: Multiple independent studies show ARL8B-dependent peripheral/anterograde lysosome positioning through BORC, SKIP/kinesin, and regulation by RNF167. supported_by: - 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:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:25898167 supporting_text: BORC acts at an early stage, recruiting Arl8b to the lysosomal membrane and therefore enabling coupling to the SKIP-Kinesin-1 complex - term: id: GO:0061909 label: autophagosome-lysosome fusion evidence_type: IMP original_reference_id: PMID:28325809 qualifier: involved_in review: summary: ARL8B contributes to autophagosome-lysosome fusion through PLEKHM1/HOPS-linked lysosomal contact sites. action: ACCEPT reason: The evidence is stronger for lysosomal tethering/fusion with autophagic cargo than for a separate autophagosome-positioning role. supported_by: - reference_id: PMID:28325809 supporting_text: Arl8b mediates recruitment of HOPS complex to PLEKHM1-positive vesicle contact sites. - reference_id: PMID:28325809 supporting_text: Arl8b binding is crucial for PLEKHM1 to promote lysosomal degradation of endocytic and autophagic cargo. - term: id: GO:1902774 label: late endosome to lysosome transport evidence_type: IMP original_reference_id: PMID:28325809 qualifier: involved_in review: summary: late endosome to lysosome transport is supported by ARL8B loss-of-function cargo-delivery assays and HOPS recruitment evidence. action: ACCEPT reason: This captures ARL8B-dependent delivery of endocytic cargo to lysosomes, a core part of its endolysosomal trafficking role. supported_by: - reference_id: PMID:21802320 supporting_text: Arl8b silencing resulted in a delay in delivery of fluid phase dextran, receptor-internalized low-density lipoprotein (LDL), and CD1 cargo to lysosomes. - reference_id: PMID:21802320 supporting_text: Arl8b was found to bind and recruit the VPS41 subunit of the HOPS (homotypic fusion and protein sorting) complex to lysosomes. - reference_id: PMID:28325809 supporting_text: Arl8b, along with its effectors, orchestrates lysosomal transport and fusion. - term: id: GO:0001778 label: plasma membrane repair evidence_type: IMP original_reference_id: PMID:29592961 qualifier: involved_in review: summary: plasma membrane repair is supported in membrane injury and Mycobacterium infection models. action: KEEP_AS_NON_CORE reason: ARL8B-dependent lysosome exocytosis is real but context-dependent, so it should be retained as non-core rather than used to define the main gene function. supported_by: - reference_id: PMID:29592961 supporting_text: Arl8b is required for the process of plasma membrane repair in controlling the Ca2+-dependent exocytosis of lysosomes - reference_id: PMID:29592961 supporting_text: Arl8b-depleted MDMs become necrotic after infection with H37Ra instead of apoptotic. - term: id: GO:0005764 label: lysosome evidence_type: IDA original_reference_id: PMID:29592961 qualifier: located_in review: summary: lysosome is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0032418 label: lysosome localization evidence_type: IMP original_reference_id: PMID:29592961 qualifier: involved_in review: summary: Lysosome localization is the best-supported core biological process for ARL8B. action: ACCEPT reason: Multiple independent studies show ARL8B-dependent peripheral/anterograde lysosome positioning through BORC, SKIP/kinesin, and regulation by RNF167. supported_by: - 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:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:25898167 supporting_text: BORC acts at an early stage, recruiting Arl8b to the lysosomal membrane and therefore enabling coupling to the SKIP-Kinesin-1 complex - term: id: GO:1990927 label: calcium ion regulated lysosome exocytosis evidence_type: IMP original_reference_id: PMID:29592961 qualifier: involved_in review: summary: calcium ion regulated lysosome exocytosis is supported in membrane injury and Mycobacterium infection models. action: KEEP_AS_NON_CORE reason: ARL8B-dependent lysosome exocytosis is real but context-dependent, so it should be retained as non-core rather than used to define the main gene function. supported_by: - reference_id: PMID:29592961 supporting_text: Arl8b is required for the process of plasma membrane repair in controlling the Ca2+-dependent exocytosis of lysosomes - term: id: GO:0002747 label: antigen processing and presentation following phagocytosis evidence_type: IMP original_reference_id: PMID:21802320 qualifier: involved_in review: summary: antigen processing and presentation following phagocytosis is supported by immune-cell lysosomal trafficking studies but is context-specific. action: KEEP_AS_NON_CORE reason: ARL8B controls delivery of antigen-containing cargo to lysosomal compartments; antigen presentation is a downstream immune-cell outcome rather than the core molecular role. supported_by: - reference_id: PMID:21802320 supporting_text: phagosome to lysosome delivery and fusion were delayed by Arl8b silencing resulting in a defect in microbial killing. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21802320 qualifier: enables review: summary: VPS41/HOPS binding supports ARL8B-mediated lysosomal cargo delivery, but protein binding is too broad and should not be treated as a useful molecular function term. action: MARK_AS_OVER_ANNOTATED reason: ARL8B functions as a regulated small GTPase that recruits specific effectors to endolysosomal membranes; a generic protein binding annotation obscures that biology and is therefore over-annotated. supported_by: - reference_id: PMID:21802320 supporting_text: Arl8b was found to bind and recruit the VPS41 subunit of the HOPS (homotypic fusion and protein sorting) complex to lysosomes. - reference_id: PMID:21802320 supporting_text: Arl8b silencing resulted in a delay in delivery of fluid phase dextran, receptor-internalized low-density lipoprotein (LDL), and CD1 cargo to lysosomes. - term: id: GO:0005525 label: GTP binding evidence_type: IMP original_reference_id: PMID:16650381 qualifier: enables review: summary: ARL8B is a small Arf-like GTPase; the GTP binding annotation is consistent with direct biochemical and sequence evidence. action: ACCEPT reason: GTP binding/hydrolysis and small G-protein switching are core molecular features of ARL8B that underlie effector recruitment on endolysosomal membranes. supported_by: - 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:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - term: id: GO:0005764 label: lysosome evidence_type: IMP original_reference_id: PMID:16650381 qualifier: located_in review: summary: lysosome is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0005764 label: lysosome evidence_type: IDA original_reference_id: PMID:21802320 qualifier: located_in review: summary: lysosome is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0019003 label: GDP binding evidence_type: IMP original_reference_id: PMID:16650381 qualifier: enables review: summary: ARL8B is a small Arf-like GTPase; the GDP binding annotation is consistent with direct biochemical and sequence evidence. action: ACCEPT reason: GTP binding/hydrolysis and small G-protein switching are core molecular features of ARL8B that underlie effector recruitment on endolysosomal membranes. supported_by: - 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:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - term: id: GO:0032418 label: lysosome localization evidence_type: IMP original_reference_id: PMID:16650381 qualifier: involved_in review: summary: Lysosome localization is the best-supported core biological process for ARL8B. action: ACCEPT reason: Multiple independent studies show ARL8B-dependent peripheral/anterograde lysosome positioning through BORC, SKIP/kinesin, and regulation by RNF167. supported_by: - 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:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:25898167 supporting_text: BORC acts at an early stage, recruiting Arl8b to the lysosomal membrane and therefore enabling coupling to the SKIP-Kinesin-1 complex - term: id: GO:0032418 label: lysosome localization evidence_type: IMP original_reference_id: PMID:21802320 qualifier: involved_in review: summary: Lysosome localization is the best-supported core biological process for ARL8B. action: ACCEPT reason: Multiple independent studies show ARL8B-dependent peripheral/anterograde lysosome positioning through BORC, SKIP/kinesin, and regulation by RNF167. supported_by: - 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:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:25898167 supporting_text: BORC acts at an early stage, recruiting Arl8b to the lysosomal membrane and therefore enabling coupling to the SKIP-Kinesin-1 complex - term: id: GO:0090117 label: endosome to lysosome transport of low-density lipoprotein particle evidence_type: IMP original_reference_id: PMID:21802320 qualifier: involved_in review: summary: endosome to lysosome transport of low-density lipoprotein particle is supported by ARL8B loss-of-function cargo-delivery assays and HOPS recruitment evidence. action: ACCEPT reason: This captures ARL8B-dependent delivery of endocytic cargo to lysosomes, a core part of its endolysosomal trafficking role. supported_by: - reference_id: PMID:21802320 supporting_text: Arl8b silencing resulted in a delay in delivery of fluid phase dextran, receptor-internalized low-density lipoprotein (LDL), and CD1 cargo to lysosomes. - term: id: GO:0090385 label: phagosome-lysosome fusion evidence_type: IMP original_reference_id: PMID:21802320 qualifier: involved_in review: summary: Phagosome-lysosome fusion is directly supported in host-defense assays, but it is a context-specific branch of ARL8B lysosomal trafficking. action: KEEP_AS_NON_CORE reason: The annotation is biologically sound, but phagocytic killing is not the broad core role of ARL8B across cell types. supported_by: - reference_id: PMID:21802320 supporting_text: phagosome to lysosome delivery and fusion were delayed by Arl8b silencing resulting in a defect in microbial killing. - term: id: GO:0002505 label: antigen processing and presentation of polysaccharide antigen via MHC class II evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: antigen processing and presentation of polysaccharide antigen via MHC class II is supported by immune-cell lysosomal trafficking studies but is context-specific. action: KEEP_AS_NON_CORE reason: ARL8B controls delivery of antigen-containing cargo to lysosomal compartments; antigen presentation is a downstream immune-cell outcome rather than the core molecular role. supported_by: - reference_id: PMID:21802320 supporting_text: Arl8b silencing resulted in a delay in delivery of fluid phase dextran, receptor-internalized low-density lipoprotein (LDL), and CD1 cargo to lysosomes. - term: id: GO:1902774 label: late endosome to lysosome transport evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: late endosome to lysosome transport is supported by ARL8B loss-of-function cargo-delivery assays and HOPS recruitment evidence. action: ACCEPT reason: This captures ARL8B-dependent delivery of endocytic cargo to lysosomes, a core part of its endolysosomal trafficking role. supported_by: - reference_id: PMID:21802320 supporting_text: Arl8b silencing resulted in a delay in delivery of fluid phase dextran, receptor-internalized low-density lipoprotein (LDL), and CD1 cargo to lysosomes. - reference_id: PMID:21802320 supporting_text: Arl8b was found to bind and recruit the VPS41 subunit of the HOPS (homotypic fusion and protein sorting) complex to lysosomes. - reference_id: PMID:28325809 supporting_text: Arl8b, along with its effectors, orchestrates lysosomal transport and fusion. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25898167 qualifier: enables review: summary: BORCS5/BORC interaction supports ARL8B lysosomal recruitment and positioning, but generic protein binding is not curator-informative. action: MARK_AS_OVER_ANNOTATED reason: ARL8B functions as a regulated small GTPase that recruits specific effectors to endolysosomal membranes; a generic protein binding annotation obscures that biology and is therefore over-annotated. supported_by: - reference_id: PMID:25898167 supporting_text: BORC functions to recruit Arl8 to lysosomes, thereby initiating a chain of interactions that promotes microtubule-guided transport of lysosomes toward the cell periphery. - reference_id: PMID:25898167 supporting_text: BORC acts at an early stage, recruiting Arl8b to the lysosomal membrane and therefore enabling coupling to the SKIP-Kinesin-1 complex - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:25898167 qualifier: colocalizes_with review: summary: lysosomal membrane is a core localization for ARL8B based on direct localization studies and UniProt synthesis. action: ACCEPT reason: ARL8B acts from lysosomal/endolysosomal membranes to recruit effectors controlling motility, tethering, fusion, and cargo sorting. supported_by: - reference_id: PMID:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - reference_id: PMID:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0032418 label: lysosome localization evidence_type: IMP original_reference_id: PMID:25898167 qualifier: involved_in review: summary: Lysosome localization is the best-supported core biological process for ARL8B. action: ACCEPT reason: Multiple independent studies show ARL8B-dependent peripheral/anterograde lysosome positioning through BORC, SKIP/kinesin, and regulation by RNF167. supported_by: - 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:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:25898167 supporting_text: BORC acts at an early stage, recruiting Arl8b to the lysosomal membrane and therefore enabling coupling to the SKIP-Kinesin-1 complex - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: Generic membrane localization from high-throughput NK-cell membrane proteomics is much less informative than lysosomal membrane localization. action: MARK_AS_OVER_ANNOTATED reason: The more specific lysosomal/cytolytic-granule membrane annotations should carry this biology; generic membrane is over-annotated. supported_by: - reference_id: PMID:19946888 supporting_text: Defining the membrane proteome of NK cells. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: Extracellular exosome comes from broad high-throughput proteomics and is not a defining ARL8B localization or function. action: MARK_AS_OVER_ANNOTATED reason: This does not fit the strong mechanistic consensus that ARL8B functions on endolysosomal/lysosomal membranes. supported_by: - reference_id: PMID:19056867 supporting_text: Large-scale proteomics and phosphoproteomics of urinary exosomes. - reference_id: file:human/ARL8B/ARL8B-uniprot.txt supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - term: id: GO:0003924 label: GTPase activity evidence_type: NAS original_reference_id: PMID:15331635 qualifier: enables review: summary: ARL8B is a small Arf-like GTPase; the GTPase activity annotation is consistent with direct biochemical and sequence evidence. action: ACCEPT reason: GTP binding/hydrolysis and small G-protein switching are core molecular features of ARL8B that underlie effector recruitment on endolysosomal membranes. supported_by: - 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:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - term: id: GO:0005525 label: GTP binding evidence_type: IDA original_reference_id: PMID:15331635 qualifier: enables review: summary: ARL8B is a small Arf-like GTPase; the GTP binding annotation is consistent with direct biochemical and sequence evidence. action: ACCEPT reason: GTP binding/hydrolysis and small G-protein switching are core molecular features of ARL8B that underlie effector recruitment on endolysosomal membranes. supported_by: - 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:16537643 supporting_text: Arl8a and Arl8b (also known as Arl10b/c and Gie1/2), localise to lysosomes in - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:15331635 qualifier: located_in review: summary: cytoplasm comes from the early GIE/ARL8B microtubule and mitosis study. action: KEEP_AS_NON_CORE reason: This appears experimentally supported but peripheral to the dominant lysosomal small-GTPase role established by later work. supported_by: - 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. - term: id: GO:0007059 label: chromosome segregation evidence_type: IMP original_reference_id: PMID:14871887 qualifier: involved_in review: summary: The term is supported by the ARL8/GIE chromosome-segregation study, but the seeded GOA original PMID points to an unrelated Drosophila Topors paper. action: KEEP_AS_NON_CORE reason: Keep as non-core because PMID:15331635 supports a mitotic phenotype for GIE/ARL8 proteins. The original_reference_id is retained as fetched GOA provenance, while the corrected supporting ARL8B reference is recorded in additional_reference_ids and the upstream source should be checked. additional_reference_ids: - PMID:15331635 supported_by: - reference_id: PMID:14871887 supporting_text: 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. - 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:0019003 label: GDP binding evidence_type: IDA original_reference_id: PMID:15331635 qualifier: enables review: summary: ARL8B is a small Arf-like GTPase; the GDP binding annotation is consistent with direct biochemical and sequence evidence. action: ACCEPT reason: GTP binding/hydrolysis and small G-protein switching are core molecular features of ARL8B that underlie effector recruitment on endolysosomal membranes. supported_by: - 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:16650381 supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution to the periphery of the cell and into membrane projections. - term: id: GO:0030496 label: midbody evidence_type: IDA original_reference_id: PMID:15331635 qualifier: located_in review: summary: midbody comes from the early GIE/ARL8B microtubule and mitosis study. action: KEEP_AS_NON_CORE reason: This appears experimentally supported but peripheral to the dominant lysosomal small-GTPase role established by later work. supported_by: - 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. - term: id: GO:0043014 label: alpha-tubulin binding evidence_type: IDA original_reference_id: PMID:15331635 qualifier: enables review: summary: alpha-tubulin binding comes from the early GIE/ARL8B microtubule and mitosis study. action: KEEP_AS_NON_CORE reason: This appears experimentally supported but peripheral to the dominant lysosomal small-GTPase role established by later work. supported_by: - 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. - term: id: GO:0048487 label: beta-tubulin binding evidence_type: IDA original_reference_id: PMID:15331635 qualifier: enables review: summary: beta-tubulin binding comes from the early GIE/ARL8B microtubule and mitosis study. action: KEEP_AS_NON_CORE reason: This appears experimentally supported but peripheral to the dominant lysosomal small-GTPase role established by later work. supported_by: - 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. - term: id: GO:0051233 label: spindle midzone evidence_type: IDA original_reference_id: PMID:15331635 qualifier: located_in review: summary: spindle midzone comes from the early GIE/ARL8B microtubule and mitosis study. action: KEEP_AS_NON_CORE reason: This appears experimentally supported but peripheral to the dominant lysosomal small-GTPase role established by later work. supported_by: - 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. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000003 title: Gene Ontology annotation based on Enzyme Commission mapping 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: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods 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: - statement: This PMID appears unrelated to ARL8B chromosome segregation and should be checked as a possible upstream GOA/UniProt reference error. supporting_text: 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. - id: PMID:15331635 title: Novel small GTPase subfamily capable of associating with tubulin is required for chromosome segregation. findings: - statement: ARL8B/GIE is a small GTPase with tubulin binding and mitotic spindle-midzone localization. supporting_text: Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis. - id: PMID:16537643 title: An N-terminally acetylated Arf-like GTPase is localised to lysosomes and affects their motility. findings: - statement: ARL8A and ARL8B localize to lysosomes and affect lysosome motility. supporting_text: Overexpression of Arl8a or Arl8b results in a microtubule-dependent redistribution of lysosomes towards the cell periphery. - id: PMID:16650381 title: The Arf-family protein, Arl8b, is involved in the spatial distribution of lysosomes. findings: - statement: GTP-locked ARL8B localizes to lysosomes and redistributes lysosomes toward the cell periphery. supporting_text: GTP-restricted mutant Arl8b localizes to lysosomes and causes their redistribution toward the cell periphery. - 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:21802320 title: Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b. findings: - statement: ARL8B is required for lysosomal cargo delivery, CD1 antigen presentation, and phagosome-lysosome fusion through VPS41/HOPS recruitment. supporting_text: Arl8b silencing resulted in a delay in delivery of fluid phase dextran, receptor-internalized low-density lipoprotein (LDL), and CD1 cargo to lysosomes. - id: PMID:22172677 title: Arl8 and SKIP act together to link lysosomes to kinesin-1. findings: - statement: ARL8 recruits SKIP/PLEKHM2 to link lysosomes to kinesin-1 for plus-end-directed movement. supporting_text: Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - id: PMID:24088571 title: Arf-like GTPase Arl8b regulates lytic granule polarization and natural killer cell-mediated cytotoxicity. findings: - statement: ARL8B promotes lytic granule and MTOC polarization required for NK-cell cytotoxicity. supporting_text: Arl8b drives the polarization of lytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse - id: PMID:25898167 title: BORC, a multisubunit complex that regulates lysosome positioning. findings: - statement: BORC recruits ARL8B to lysosomes to promote microtubule-guided peripheral lysosome transport. supporting_text: BORC functions to recruit Arl8 to lysosomes, thereby initiating a chain of interactions that promotes microtubule-guided transport of lysosomes toward the cell periphery. - id: PMID:27808481 title: RNF167 targets Arl8B for degradation to regulate lysosome positioning and endocytic trafficking. findings: - statement: RNF167 ubiquitinates ARL8B and thereby regulates ARL8B-dependent lysosome positioning. supporting_text: RNF167 ubiquitinates Arl8B at the lysine residue K141 and reduces the level of the Arl8B protein. - id: PMID:28325809 title: The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traffic to lysosomes. findings: - statement: PLEKHM1 connects Rab7 and ARL8B to recruit HOPS and promote lysosomal degradation of endocytic and autophagic cargo. supporting_text: Arl8b binding is crucial for PLEKHM1 to promote lysosomal degradation of endocytic and autophagic cargo. - id: PMID:29592961 title: Lysosome-Mediated Plasma Membrane Repair Is Dependent on the Small GTPase Arl8b and Determines Cell Death Type in Mycobacterium tuberculosis Infection. findings: - statement: ARL8B-dependent lysosome exocytosis supports plasma membrane repair during Mycobacterium infection. supporting_text: Arl8b is required for the process of plasma membrane repair in controlling the Ca2+-dependent exocytosis of lysosomes - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:33157038 title: β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway. findings: - statement: Beta-coronaviruses use an ARL8B-dependent lysosomal exocytic egress pathway. supporting_text: these viruses use a lysosomal, Arl8b-dependent exocytic pathway for release into the extracellular environment. - id: PMID:35314674 title: RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin. findings: - statement: RUFY3 and RUFY4 are ARL8 effectors that couple endolysosomes to dynein-dynactin for retrograde transport. supporting_text: RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin - id: PMID:36282215 title: RUFY1 binds Arl8b and mediates endosome-to-TGN CI-M6PR retrieval for cargo sorting to lysosomes. findings: - statement: ARL8B regulates RUFY1 endosomal localization and CI-M6PR retrieval from endosomes to the TGN. supporting_text: RUFY1 depletion led to a delay in CI-M6PR retrieval from endosomes to the TGN, resulting in impaired delivery of newly synthesized hydrolases to lysosomes. - 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 a direct ARL8B effector recruited to peripheral lysosomes, where it acts as a GEF for Rab34; activated Rab34 recruits a RILP/dynein complex to drive retrograde lysosome transport and nutrient-dependent juxtanuclear repositioning, and loss of DENND6A impairs autophagic flux. This positions ARL8B as a bidirectional transport coordinator, distinct from the RUFY3/RUFY4 dynein-dynactin coupling. - 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 cause an infantile-onset neurodegenerative disorder; BORC sequentially recruits ARL8 and kinesin motors to lysosomes, and variant alleles reduce BORC assembly and peripheral lysosome distribution. This is human disease evidence for the upstream BORC-to-ARL8B anterograde axis, but concerns BORCS8 rather than an ARL8B coding mutation. - id: file:human/ARL8B/ARL8B-uniprot.txt title: UniProtKB reviewed entry for human ARL8B (Q9NVJ2) findings: - statement: Reviewed UniProt synthesis places ARL8B on lysosomal/endolysosomal membranes as a small GTPase controlling lysosomal positioning, transport, fusion, and exocytosis. supporting_text: Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv title: Proteostasis PN projected candidate additions for ARL8B findings: - statement: The PN projection suggests ARL8B to GO:0061906 autophagosome localization, but the gene-specific review treats this conservatively because direct evidence is stronger for lysosome localization and autophagosome-lysosome fusion. supporting_text: "ARL8B\t\tGO:0061906\tautophagosome localization\tnew_to_goa" core_functions: - description: ARL8B is an endolysosomal small GTPase that uses GTP-dependent effector recruitment to control lysosome positioning and lysosome-centered cargo delivery. Its best-supported core role is coordinating lysosome movement and contact/fusion machinery, including BORC/SKIP-kinesin positioning and PLEKHM1/HOPS-dependent delivery of endocytic, phagocytic, and autophagic cargo to lysosomes. molecular_function: id: GO:0003924 label: GTPase activity directly_involved_in: - id: GO:0032418 label: lysosome localization - id: GO:1902774 label: late endosome to lysosome transport - id: GO:0061909 label: autophagosome-lysosome fusion locations: - id: GO:0005765 label: lysosomal membrane - id: GO:0031902 label: late endosome membrane - id: GO:0031901 label: early endosome membrane supported_by: - 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:22172677 supporting_text: Thus, Arl8 binding to SKIP provides a link from lysosomal membranes to plus-end-directed motility. - reference_id: PMID:21802320 supporting_text: Arl8b silencing resulted in a delay in delivery of fluid phase dextran, receptor-internalized low-density lipoprotein (LDL), and CD1 cargo to lysosomes. - reference_id: PMID:28325809 supporting_text: Arl8b binding is crucial for PLEKHM1 to promote lysosomal degradation of endocytic and autophagic cargo. - reference_id: PMID:25898167 supporting_text: BORC functions to recruit Arl8 to lysosomes, thereby initiating a chain of interactions that promotes microtubule-guided transport of lysosomes toward the cell periphery. proposed_new_terms: [] suggested_questions: - question: Should ARL8B be annotated directly to GO:0061906 autophagosome localization from the PN HOPS-BORC bridging projection, or is the current direct evidence better captured by lysosome localization and autophagosome-lysosome fusion? - question: Can the upstream reference for the GO:0007059 chromosome segregation annotation be corrected from PMID:14871887 to the ARL8B/GIE study PMID:15331635? - question: Which ARL8B effector branch should be considered core for general gene-product curation versus cell-type-specific extensions such as NK-cell granule polarization, Mtb membrane repair, or beta-coronavirus egress? - question: Should ARL8B be annotated to retrograde lysosome transport given that it now has two distinct retrograde effector branches (DENND6A/Rab34/RILP/dynein and RUFY3/RUFY4/dynein-dynactin), and how should these be distinguished from the better-established anterograde SKIP/kinesin role? suggested_experiments: - description: Separate ARL8B lysosome-positioning effects from autophagosome-positioning effects by live imaging of autophagosomes and lysosomes after ARL8B depletion or effector-selective rescue. hypothesis: The PN autophagosome-localization signal is mainly an indirect consequence of ARL8B-dependent lysosome positioning and HOPS-mediated fusion rather than direct autophagosome positioning. - description: Use effector-binding mutants of ARL8B to compare PLEKHM2/SKIP, PLEKHM1/HOPS, VPS41, RUFY1, RUFY3/4, and DENND6A outputs in the same cellular background. hypothesis: Distinct ARL8B effector interfaces partition lysosome positioning, cargo delivery, and lysosome exocytosis functions. - description: Test whether ARL8B-dependent retrograde lysosome transport requires the DENND6A/Rab34/RILP/dynein cascade by measuring nutrient-dependent juxtanuclear lysosome repositioning and autophagic flux after depletion of DENND6A, Rab34, or RILP versus RUFY3/4. hypothesis: ARL8B initiates retrograde lysosome transport through at least two parallel dynein-recruiting branches (DENND6A/Rab34/RILP and RUFY3/4), and these jointly regulate nutrient-responsive lysosome positioning and autophagy. tags: - proteostasis - autophagy-lysosome-pathway - lysosome-positioning - pn-projection-reviewed