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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005765 lysosomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: ARL8A lysosomal membrane localization is a core, well-supported location. 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. Supporting Evidence: PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells PMID:25898167 two paralogs of Arl8 (Arl8a and Arl8b) are the only ones known to associate specifically with lysosomes PMID:35314674 ARL8A and ARL8B paralogs ... are unique in their ability to associate with endolysosomes |
| GO:0008089 anterograde axonal transport | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Anterograde axonal transport is plausible for ARL8-family endolysosomal transport but is a neuron-specific manifestation of the broader lysosome/endolysosome motility role. 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. Supporting Evidence: PMID:25898167 This initiates a chain of interactions that promotes the kinesin-dependent movement of lysosomes toward the plus ends of microtubules PMID:35314674 ARL8 can thus regulate both anterograde and retrograde endolysosome transport through interactions with kinesin and dynein-dynactin motors PMID:35314674 toward the distal axon in neurons |
| GO:0003924 GTPase activity | IEA GO_REF:0000002 | ACCEPT | Summary: GTPase activity is consistent with ARL8A being an ARF-family small GTPase. 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. Supporting Evidence: PMID:15331635 Here, we identify novel GTPases (human Gie1 and Gie2) that form a distinct subfamily of the small GTPases PMID:35314674 Like other small GTPases, ARL8 cycles between GDP-bound, inactive, and GTP-bound, active forms |
| GO:0005525 GTP binding | IEA GO_REF:0000002 | ACCEPT | Summary: GTP binding is consistent with ARL8A being an ARF-family small GTPase. 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. Supporting Evidence: PMID:15331635 Here, we identify novel GTPases (human Gie1 and Gie2) that form a distinct subfamily of the small GTPases PMID:35314674 Like other small GTPases, ARL8 cycles between GDP-bound, inactive, and GTP-bound, active forms |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ARL8A lysosomal membrane localization is a core, well-supported location. 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. Supporting Evidence: PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells PMID:25898167 two paralogs of Arl8 (Arl8a and Arl8b) are the only ones known to associate specifically with lysosomes PMID:35314674 ARL8A and ARL8B paralogs ... are unique in their ability to associate with endolysosomes |
| GO:0005819 spindle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: spindle reflects the older GIE/ARL8 mitotic localization study and is not the proteostasis-centered ARL8A role. 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. Supporting Evidence: PMID:15331635 Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis PMID:15331635 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 |
| GO:0015031 protein transport | IEA GO_REF:0000002 | MODIFY | Summary: Generic protein transport is too broad for the ARL8A evidence. 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 replacements: lysosome localization Supporting Evidence: PMID:16537643 Live cell imaging shows that lysosomes move more frequently both toward and away from the cell periphery PMID:25898167 This initiates a chain of interactions that promotes the kinesin-dependent movement of lysosomes toward the plus ends of microtubules PMID:35314674 ARL8 can thus regulate both anterograde and retrograde endolysosome transport through interactions with kinesin and dynein-dynactin motors |
| GO:0030424 axon | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: axon is a plausible neuronal context for ARL8-family endolysosomal transport but not the core PN function. 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. Supporting Evidence: PMID:35314674 toward the distal axon in neurons PMID:35314674 RUFY3 and RUFY4 promote retrograde transport of ARL8-positive endolysosomal vesicles from the axon to the soma |
| GO:0031902 late endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Late endosome membrane is a reasonable endolysosomal ARL8A location. 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. Supporting Evidence: PMID:35314674 endolysosomes broadly to denote various types of lysosomes, late endosomes, and related endolysosomal organelles PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells |
| GO:0045202 synapse | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: synapse is a plausible neuronal context for ARL8-family endolysosomal transport but not the core PN function. 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. Supporting Evidence: PMID:35314674 toward the distal axon in neurons PMID:35314674 RUFY3 and RUFY4 promote retrograde transport of ARL8-positive endolysosomal vesicles from the axon to the soma |
| GO:0051233 spindle midzone | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: spindle midzone reflects the older GIE/ARL8 mitotic localization study and is not the proteostasis-centered ARL8A role. 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. Supporting Evidence: PMID:15331635 Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis PMID:15331635 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 |
| GO:1904115 axon cytoplasm | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: axon cytoplasm is a plausible neuronal context for ARL8-family endolysosomal transport but not the core PN function. 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. Supporting Evidence: PMID:35314674 toward the distal axon in neurons PMID:35314674 RUFY3 and RUFY4 promote retrograde transport of ARL8-positive endolysosomal vesicles from the axon to the soma |
| GO:0005515 protein binding | IPI PMID:24955142 Exploration of panviral proteome: high-throughput cloning an... | REMOVE | Summary: Protein binding is an uninformative representation of ARL8A interaction data. 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. Supporting Evidence: PMID:24955142 Exploration of panviral proteome: high-throughput cloning and functional implications in virus-host interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein binding is an uninformative representation of ARL8A interaction data. 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. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:28325809 The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traff... | REMOVE | Summary: Protein binding is an uninformative representation of ARL8A interaction data. 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. Supporting Evidence: PMID:28325809 PLEKHM1 directly binds to Arl8b via its N-terminal RUN domain-containing region |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding is an uninformative representation of ARL8A interaction data. 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. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Protein binding is an uninformative representation of ARL8A interaction data. 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. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Protein binding is an uninformative representation of ARL8A interaction data. 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. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics. |
| GO:0008089 anterograde axonal transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Anterograde axonal transport is plausible for ARL8-family endolysosomal transport but is a neuron-specific manifestation of the broader lysosome/endolysosome motility role. 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. Supporting Evidence: PMID:25898167 This initiates a chain of interactions that promotes the kinesin-dependent movement of lysosomes toward the plus ends of microtubules PMID:35314674 ARL8 can thus regulate both anterograde and retrograde endolysosome transport through interactions with kinesin and dynein-dynactin motors PMID:35314674 toward the distal axon in neurons |
| GO:0005765 lysosomal membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ARL8A lysosomal membrane localization is a core, well-supported location. 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. Supporting Evidence: PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells PMID:25898167 two paralogs of Arl8 (Arl8a and Arl8b) are the only ones known to associate specifically with lysosomes PMID:35314674 ARL8A and ARL8B paralogs ... are unique in their ability to associate with endolysosomes |
| GO:0031902 late endosome membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Late endosome membrane is a reasonable endolysosomal ARL8A location. 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. Supporting Evidence: PMID:35314674 endolysosomes broadly to denote various types of lysosomes, late endosomes, and related endolysosomal organelles PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells |
| GO:0045202 synapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: synapse is a plausible neuronal context for ARL8-family endolysosomal transport but not the core PN function. 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. Supporting Evidence: PMID:35314674 toward the distal axon in neurons PMID:35314674 RUFY3 and RUFY4 promote retrograde transport of ARL8-positive endolysosomal vesicles from the axon to the soma |
| GO:0005515 protein binding | IPI PMID:35314674 RUFY3 and RUFY4 are ARL8 effectors that promote coupling of ... | REMOVE | Summary: Protein binding is an uninformative representation of ARL8A interaction data. 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. Supporting Evidence: PMID:35314674 both RUFY3.1 and RUFY4 have the ability to interact with GTP-bound, but not GDP-bound, ARL8 |
| GO:0005515 protein binding | IPI PMID:25898167 BORC, a multisubunit complex that regulates lysosome positio... | REMOVE | Summary: Protein binding is an uninformative representation of ARL8A interaction data. 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. Supporting Evidence: PMID:25898167 BORC functions to recruit Arl8 to lysosomes |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6798739 | REMOVE | Summary: plasma membrane is a Reactome granule-exocytosis context and is not supported as an ARL8A steady-state location. 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. Supporting Evidence: Reactome:R-HSA-6798739 Azurophil granules undergo limited exocytosis in response to stimulation PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells PMID:25898167 two paralogs of Arl8 (Arl8a and Arl8b) are the only ones known to associate specifically with lysosomes |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6800426 | REMOVE | Summary: plasma membrane is a Reactome granule-exocytosis context and is not supported as an ARL8A steady-state location. 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. Supporting Evidence: Reactome:R-HSA-6800426 Ficolin-1 rich granules can be differentiated by having low levels of gelatinases and an elevated exocytosis propensity PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells PMID:25898167 two paralogs of Arl8 (Arl8a and Arl8b) are the only ones known to associate specifically with lysosomes |
| GO:0035577 azurophil granule membrane | TAS Reactome:R-HSA-6798739 | REMOVE | Summary: azurophil granule membrane is a Reactome granule-exocytosis context and is not supported as an ARL8A steady-state location. 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. Supporting Evidence: Reactome:R-HSA-6798739 Azurophil granules undergo limited exocytosis in response to stimulation PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells PMID:25898167 two paralogs of Arl8 (Arl8a and Arl8b) are the only ones known to associate specifically with lysosomes |
| GO:0101003 ficolin-1-rich granule membrane | TAS Reactome:R-HSA-6800426 | REMOVE | Summary: ficolin-1-rich granule membrane is a Reactome granule-exocytosis context and is not supported as an ARL8A steady-state location. 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. Supporting Evidence: Reactome:R-HSA-6800426 Ficolin-1 rich granules can be differentiated by having low levels of gelatinases and an elevated exocytosis propensity PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells PMID:25898167 two paralogs of Arl8 (Arl8a and Arl8b) are the only ones known to associate specifically with lysosomes |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: Membrane is a broad high-throughput location that should be kept only as non-core context. 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. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells. PMID:35314674 the GTP-bound form associates with endolysosomes |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: Extracellular exosome is a high-throughput proteomics context without clear ARL8A functional support. 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. Supporting Evidence: PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes. PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells PMID:25898167 two paralogs of Arl8 (Arl8a and Arl8b) are the only ones known to associate specifically with lysosomes |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | ACCEPT | Summary: Lysosomal membrane is supported by lysosomal membrane proteomics and by direct ARL8 lysosome-localization studies. 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. Supporting Evidence: PMID:17897319 We searched for novel proteins in lysosomal membranes PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells PMID:25898167 two paralogs of Arl8 (Arl8a and Arl8b) are the only ones known to associate specifically with lysosomes |
| GO:0003924 GTPase activity | NAS PMID:15331635 Novel small GTPase subfamily capable of associating with tub... | ACCEPT | Summary: GTPase activity is consistent with ARL8A being an ARF-family small GTPase. 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. Supporting Evidence: PMID:15331635 Here, we identify novel GTPases (human Gie1 and Gie2) that form a distinct subfamily of the small GTPases PMID:35314674 Like other small GTPases, ARL8 cycles between GDP-bound, inactive, and GTP-bound, active forms |
| GO:0005525 GTP binding | IDA PMID:15331635 Novel small GTPase subfamily capable of associating with tub... | ACCEPT | Summary: GTP binding is consistent with ARL8A being an ARF-family small GTPase. 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. Supporting Evidence: PMID:15331635 Here, we identify novel GTPases (human Gie1 and Gie2) that form a distinct subfamily of the small GTPases PMID:35314674 Like other small GTPases, ARL8 cycles between GDP-bound, inactive, and GTP-bound, active forms |
| GO:0005737 cytoplasm | IDA PMID:15331635 Novel small GTPase subfamily capable of associating with tub... | KEEP AS NON CORE | Summary: Cytoplasm is a broad localization from the original GIE study and is non-core relative to lysosomal/endolysosomal membranes. 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. Supporting Evidence: PMID:35314674 Whereas the GDP-bound form is cytosolic, the GTP-bound form associates with endolysosomes PMID:16537643 Arl8a and Arl8b ... localise to lysosomes in mammalian cells |
| GO:0007059 chromosome segregation | ISS PMID:14871887 Drosophila Topors is a RING finger-containing protein that f... | KEEP AS NON CORE | Summary: Chromosome segregation is a plausible but non-core mitotic ARL8/GIE role; the original GOA PMID is not the relevant ARL8 paper. 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. Supporting Evidence: PMID:14871887 Drosophila Topors is a RING finger-containing protein PMID:15331635 Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis PMID:15331635 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 |
| GO:0030496 midbody | IDA PMID:15331635 Novel small GTPase subfamily capable of associating with tub... | KEEP AS NON CORE | Summary: midbody reflects the older GIE/ARL8 mitotic localization study and is not the proteostasis-centered ARL8A role. 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. Supporting Evidence: PMID:15331635 Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis PMID:15331635 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 |
| GO:0043014 alpha-tubulin binding | ISS PMID:15331635 Novel small GTPase subfamily capable of associating with tub... | KEEP AS NON CORE | Summary: alpha-tubulin binding is supported by the GIE/ARL8 tubulin-association study but is 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. Supporting Evidence: PMID:15331635 Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis PMID:15331635 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 |
| GO:0048487 beta-tubulin binding | ISS PMID:15331635 Novel small GTPase subfamily capable of associating with tub... | KEEP AS NON CORE | Summary: beta-tubulin binding is supported by the GIE/ARL8 tubulin-association study but is 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. Supporting Evidence: PMID:15331635 Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis PMID:15331635 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 |
| GO:0051233 spindle midzone | IDA PMID:15331635 Novel small GTPase subfamily capable of associating with tub... | KEEP AS NON CORE | Summary: spindle midzone reflects the older GIE/ARL8 mitotic localization study and is not the proteostasis-centered ARL8A role. 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. Supporting Evidence: PMID:15331635 Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis PMID:15331635 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 |
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Download this section (compressed HTML)Q: 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?
Suggested experts: GO autophagy editors, GO proteostasis PN curators
Q: Should broad ARL8A protein binding annotations be replaced by a more specific curator model of small-GTPase effector recruitment for lysosome/endolysosome transport?
Suggested experts: GO molecular function editors, UniProt curators
Q: 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?
Suggested experts: GO lysosome/membrane trafficking curators, lysosomal lipid trafficking experts
Experiment: 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.
Hypothesis: ARL8A regulates lysosome/endolysosome positioning but does not directly position autophagosomes independently of ARL8B or lysosome movement.
Type: ARL8A-specific autophagosome positioning assay
Experiment: 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.
Hypothesis: ARL8A effector binding to PLEKHM1/HOPS, SKIP, and RUFY3/RUFY4 separates lysosome localization, anterograde movement, retrograde movement, and autophagic cargo-delivery phenotypes.
Type: Effector-binding separation of function
Experiment: 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.
Hypothesis: ARL8A contributes to BORC-ARL8-HOPS-dependent lysosomal cholesterol egress and to endolysosome fusion that restrains exosome secretion, with partial redundancy with ARL8B.
Type: ARL8A-specific cholesterol egress and exosome secretion assay
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