Existing Annotations Review

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

Core Functions

ARL8A is a lysosomal/late-endosomal small GTPase that regulates endolysosome positioning and microtubule-based motility through BORC-dependent membrane recruitment and GTP-dependent effector interactions. This core activity supports lysosome localization, endolysosomal cargo delivery to lysosomes, and lysosome-related vesicle transport in specialized cellular contexts.

Molecular Function:

GTPase activity

Directly Involved In:

lysosome localization

Cellular Locations:

lysosomal membrane late endosome membrane

Supporting Evidence:

PMID:16537643
Arl8a and Arl8b ... localise to lysosomes in mammalian cells
PMID:16537643
Overexpression of Arl8a or Arl8b results in a microtubule-dependent redistribution of lysosomes towards the cell periphery
PMID:25898167
BORC associates peripherally with the lysosomal membrane, where it functions to recruit the small GTPase Arl8
PMID:28325809
Arl8b binding to PLEKHM1 is required for its function in delivery and, therefore, degradation of endocytic and autophagic cargo in lysosomes
PMID:35314674
RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:14871887

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.

PMID:15331635

Novel small GTPase subfamily capable of associating with tubulin is required for chromosome segregation.

PMID:17897319

Integral and associated lysosomal membrane proteins.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:24955142

Exploration of panviral proteome: high-throughput cloning and functional implications in virus-host interactions.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25898167

BORC, a multisubunit complex that regulates lysosome positioning.

PMID:28325809

The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traffic to lysosomes.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35314674

RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:27851960

BORC Functions Upstream of Kinesins 1 and 3 to Coordinate Regional Movement of Lysosomes along Different Microtubule Tracks.

BORC and ARL8 act upstream of both kinesin-1 (KIF5B) and kinesin-3 (KIF1A/KIF1Bbeta), which move lysosomes on distinct microtubule tracks (KIF5B on central acetylated tubulin, KIF1A/KIF1Bbeta on peripheral tyrosinated tubulin); in an ARL8B-knockout background, siRNA against ARL8A removes the residual ability of kinesin constructs to disperse lysosomes, indicating ARL8A itself contributes to BORC-dependent anterograde lysosome transport.

PMID:35653304

BORC-ARL8-HOPS ensemble is required for lysosomal cholesterol egress through NPC2.

The BORC-ARL8-HOPS ensemble is required for egress of free cholesterol from lysosomes; depletion of BORC, ARL8, or HOPS causes lysosomal free-cholesterol accumulation, decreased NPC2 association with lysosomes with increased NPC2 secretion, and increased lysosomal degradation of the CI-mannose-6-phosphate receptor.

PMID:37213076

Inhibition of endolysosome fusion increases exosome secretion.

Impairing the BORC-ARL8-HOPS pathway blocks fusion of multivesicular endosomes with lysosomes and increases exosome secretion; the study used HeLa ARL8A/ARL8B double-knockout cells, indicating an ARL8-family requirement for endolysosome fusion that determines exosome output.

PMID:38296963

DENND6A links Arl8b to a Rab34/RILP/dynein complex, regulating lysosomal positioning and autophagy.

DENND6A is an ARL8B effector and GEF that activates Rab34 to recruit a RILP/dynein-dynactin complex, driving retrograde (juxtanuclear) lysosome transport and supporting autophagic flux; double knockdown of ARL8A and ARL8B reduces DENND6A-dependent phenotypes, consistent with an ARL8-family contribution.

PMID:38128568

Biallelic BORCS8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics.

Biallelic loss-of-function variants in the BORC subunit BORCS8 (which acts upstream of ARL8 to recruit kinesin motors for anterograde lysosome transport) cause a severe early-infantile neurodegenerative disorder in five children; patient alleles impair BORC assembly and peripheral lysosome distribution, validating the BORC-ARL8-kinesin axis physiologically in humans.

PMID:39217195

Altered expression of vesicular trafficking machinery in prostate cancer affects lysosomal dynamics and provides insight into the underlying biology and disease progression.

In prostate cancer cohorts, altered expression of lysosomal trafficking machinery including ARL8A was examined; ARL8A expression showed only a non-significant association with overall survival (log-rank P=0.1471, HR 1.927, 95% CI 0.6692-5.547).

Reactome:R-HSA-6798739

Exocytosis of azurophil granule membrane proteins

Reactome:R-HSA-6800426

Exocytosis of ficolin-rich granule membrane proteins

PMID:16537643

An N-terminally acetylated Arf-like GTPase is localised to lysosomes and affects their motility.

file:human/ARL8A/ARL8A-uniprot.txt

UniProtKB record for human ARL8A

file:human/ARL8A/ARL8A-notes.md

ARL8A PN-context review notes

file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_new_to_goa.tsv

PN projected new-to-GOA annotations report

file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

PN mapping scrutiny report

Suggested Experiments

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

Deep Research

Falcon

(ARL8A-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 35 citations 2 artifacts 2026-06-07T04:34:42.311811

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000031 The Kaplan–Meier plot for ARL8A from Figure 3 is extracted, showing the overall survival rate with a log-rank P = 0.1471 and HR (95 (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human ARL8A (UniProt Q96BM9) — functional annotation

1) Target verification (gene/protein identity and disambiguation)

Target: Homo sapiens ARL8A (UniProt Q96BM9), a small Arf-family GTPase, also described as ADP-ribosylation factor-like protein 8A. ARL8A is one of two vertebrate paralogs (ARL8A and ARL8B) that are ~91% identical and are generally treated as an ARL8 family module regulating lysosome dynamics. (rizalar2022investigationofbiogenesis pages 30-33, khatter2015arflikegtpasearl8 pages 5-8)

Disambiguation note: The strongest mechanistic literature base is for ARL8B, but multiple key studies and reviews explicitly treat ARL8A/ARL8B together (e.g., combined knockdown/double KO), and ARL8A is consistently described as a lysosome-localized paralog with overlapping effector interactions and functions. Where evidence is ARL8B-only, this report flags it as paralog-inferred for ARL8A. (khatter2015arflikegtpasearl8 pages 5-8, shelke2023inhibitionofendolysosome pages 1-2, guardia2016borcfunctionsupstream pages 5-6)

2) Key concepts and definitions (current understanding)

2.1 ARL8A is a lysosome-associated small GTPase

ARL8A (with ARL8B) is described as a conserved small GTPase that localizes to lysosomes (co-localizing with lysosomal markers such as CD63 and LAMP2, not early endosome marker EEA1). (rizalar2022investigationofbiogenesis pages 30-33)

Membrane targeting mechanism: Unlike many Arf-family proteins, ARL8 proteins do not use a canonical N-myristoyl glycine at position 2; instead they have an N-terminal amphipathic helix and are described as relying on N-terminal acetylation (NatC) for proper membrane targeting to lysosomes. (khatter2015arflikegtpasearl8 pages 5-8, rizalar2022investigationofbiogenesis pages 30-33)

2.2 Functional definition: “Master organizer” of lysosome positioning and trafficking

Across foundational reviews and mechanistic studies, ARL8 proteins are positioned as central regulators that:
1) couple lysosomes/endolysosomes to microtubule motors for long-range movement, and
2) promote fusion/tethering of late endocytic carriers with lysosomes through recruitment of tethering factors. (khatter2015arflikegtpasearl8 pages 8-10, guardia2016borcfunctionsupstream pages 1-3)

3) Molecular mechanism and pathways (primary function, partners, localization)

3.1 Upstream recruitment to lysosomes: BORC → ARL8

A core organizing pathway is BORC → ARL8 → motor/tether recruitment. BORC is an 8-subunit complex on the cytosolic face of lysosomes that functions upstream to recruit ARL8 proteins, enabling outward transport. Loss of BORC subunits detaches ARL8 from lysosomes and causes juxtanuclear lysosome clustering. (khatter2015arflikegtpasearl8 pages 5-8, guardia2016borcfunctionsupstream pages 5-6)

Guardia et al. (Cell Reports, 2016-11; https://doi.org/10.1016/j.celrep.2016.10.062) experimentally place BORC upstream of ARL8 and show that BORC-dependent ARL8 function is required for kinesin-dependent lysosome dispersal; critically, in an ARL8B-KO background, siRNA against ARL8A removes the residual ability of kinesin constructs to disperse lysosomes, directly supporting that both ARL8A and ARL8B contribute to the transport program. (guardia2016borcfunctionsupstream pages 5-6)

3.2 Anterograde (plus-end) lysosome transport: ARL8-GTP → SKIP/PLEKHM2 → kinesin-1

Primary transport function: In the GTP-bound state, ARL8 recruits SKIP/PLEKHM2, which binds kinesin light chain KLC2 and enables kinesin-1 (KIF5B)-driven plus-end movement of lysosomes toward the cell periphery. Depletion of ARL8B or SKIP (and family-level ARL8 perturbation) leads to perinuclear lysosome clustering, while overexpression of ARL8 proteins or SKIP promotes peripheral redistribution. (khatter2015arflikegtpasearl8 pages 8-10, rizalar2022investigationofbiogenesis pages 30-33, guardia2016borcfunctionsupstream pages 4-5)

Quantitative phenotype example: In HeLa cells, knockdown of KIF5B or KIF1B caused lysosome clustering/“collapse” in ~40% and ~85% of cells, respectively, highlighting the major role of kinesins in centrifugal lysosome positioning downstream of ARL8/BORC. (guardia2016borcfunctionsupstream pages 4-5)

3.3 Kinesin-3 coupling and track specialization: ARL8 → KIF1A/KIF1Bβ

BORC and ARL8 function upstream of both kinesin-1 and kinesin-3 classes. Guardia et al. show kinesin-1 (KIF5B) and kinesin-3 (KIF1A/KIF1Bβ) can drive lysosome dispersal but operate on different microtubule subsets: KIF5B is enriched on more central acetylated tracks, whereas KIF1A/KIF1Bβ aligns with more peripheral tyrosinated tracks—supporting a “regional transport routing” model for lysosomes. (guardia2016borcfunctionsupstream pages 1-3, guardia2016borcfunctionsupstream pages 10-11)

Shelke et al. (J Cell Biol, 2023-05; https://doi.org/10.1083/jcb.202209084) further summarize that ARL8 effectors include motor-coupling partners for both anterograde and retrograde programs, including direct kinesin-3 coupling (KIF1A/KIF1Bβ) within the BORC–ARL8 pathway framework. (shelke2023inhibitionofendolysosome pages 1-2)

ARL8 proteins are also described as recruiting HOPS tethering components to lysosomes to promote fusion with late endosomes and autophagic cargo carriers, impacting degradative trafficking (e.g., delivery of endocytic cargo and receptor downregulation). This is emphasized in authoritative reviews as a central lysosomal function of ARL8, though often demonstrated most directly for ARL8B. (khatter2015arflikegtpasearl8 pages 8-10, sharma2019emergingrolesof pages 10-11)

A concrete pathway readout of ARL8–HOPS function is cholesterol handling:
- Anderson et al. (Mol Biol Cell, 2022-08; https://doi.org/10.1091/mbc.e21-11-0595-t) show that depletion/KO of BORC, ARL8, or HOPS causes free cholesterol accumulation in lysosomes, reduced cholesteryl ester storage, decreased association of luminal cholesterol transporter NPC2 with lysosomes, increased NPC2 secretion, and increased lysosomal degradation of CI-MPR. The authors conclude the BORC–ARL8–HOPS ensemble is required for NPC2 trafficking and cholesterol egress. (anderson2022borcarl8hopsensembleis pages 1-2)

3.5 Bidirectional lysosome positioning (2024 update): ARL8 also contributes to retrograde programs

While ARL8 is historically framed as an anterograde lysosome dispersal GTPase, recent work expands ARL8-associated machinery to include retrograde positioning programs:
- Kumar et al. (Nat Commun, 2024-01; https://doi.org/10.1038/s41467-024-44957-1) identify DENND6A as an ARL8B effector that activates Rab34, leading to recruitment of RILP/dynein-dynactin and retrograde lysosome transport. Loss of DENND6A impairs autophagic flux readouts (LC3B-II changes under EBSS ± BafA1) and disrupts degradative trafficking. Although centered on ARL8B, the study reports that double knockdown of ARL8A and ARL8B reduces DENND6A localization phenotypes, consistent with an ARL8-family requirement for this positioning cascade. (kumar2024dennd6alinksarl8b pages 12-13)

4) Recent developments and latest research (prioritizing 2023–2024)

4.1 Exosome secretion controlled by BORC–ARL8–HOPS-dependent endolysosome fusion (2023)

Shelke et al. (J Cell Biol, 2023-05; https://doi.org/10.1083/jcb.202209084) show that disruption of BORC–ARL8–HOPS increases exosome secretion, interpreted as impaired fusion of multivesicular endosomes with lysosomes, leaving intraluminal vesicles available for extracellular release. This work used ARL8A/ARL8B double knockout HeLa models as part of the mechanistic perturbation set, making it particularly relevant to ARL8A (not just ARL8B). (shelke2023inhibitionofendolysosome pages 1-2)

4.2 Human genetics links lysosome positioning machinery upstream of ARL8A to neurodevelopment (2024)

De Pace et al. (Brain, 2024-12; https://doi.org/10.1093/brain/awad427) report biallelic BORCS8 variants in five children from three families with severe early-infantile neurodegenerative/neurodevelopmental disease. The paper frames BORC as an upstream lysosomal complex that recruits ARL8 and kinesin motors to drive anterograde lysosome transport to the periphery and distal axon, and shows patient variants impair BORC assembly/function and reduce the ability to restore peripheral lysosome distribution in BORCS8-KO cells. (pace2024biallelicborcs8variants pages 1-2, pace2024biallelicborcs8variants pages 15-16)

This provides strong translational evidence that the BORC→ARL8→kinesin axis is physiologically critical in humans, even though the causal gene in this study is upstream of ARL8A itself. (pace2024biallelicborcs8variants pages 1-2)

4.3 Cancer cohort associations (2024): ARL8A expression shows a non-significant survival trend

Nturubika et al. (Br J Cancer, 2024-08; https://doi.org/10.1038/s41416-024-02829-x) examined lysosomal trafficking gene expression in prostate cancer cohorts. In Kaplan–Meier analyses, ARL8A showed a non-significant association with outcome (Log-rank P = 0.1471, HR = 1.927, 95% CI 0.6692–5.547) in the plotted cohort context. (nturubika2024alteredexpressionof pages 5-5, nturubika2024alteredexpressionof media 25d4e50c)

5) Current applications and real-world implementations

5.1 Research-use manipulation of lysosome positioning and function

Across modern cell biology, ARL8 pathway components are used as experimental control points to:
- reposition lysosomes (peripheral vs juxtanuclear),
- modulate endolysosomal fusion (via HOPS recruitment pathways),
- influence exosome secretion (via endolysosome fusion competence), and
- modulate cholesterol egress phenotypes (NPC2 trafficking) and degradative flux. (shelke2023inhibitionofendolysosome pages 1-2, anderson2022borcarl8hopsensembleis pages 1-2, guardia2016borcfunctionsupstream pages 5-6)

5.2 Translational maturity

Within the retrieved literature set, there is no evidence of an approved ARL8A-targeted therapy or diagnostic. Translational relevance is presently strongest at the pathway level (BORC/ARL8/HOPS/motor systems) in neurodevelopmental disease mechanisms and in cancer lysosome biology hypotheses. (pace2024biallelicborcs8variants pages 1-2, nturubika2024alteredexpressionof pages 5-5)

6) Expert opinions / authoritative synthesis

Two influential syntheses frame ARL8 proteins as central lysosomal regulators:
- Khatter et al. (Cellular Logistics, 2015-07; https://doi.org/10.1080/21592799.2015.1086501) emphasize ARL8 as moving “to the center of lysosomal biology,” highlighting lysosome motility and fusion functions and the key effectors SKIP (kinesin-1 coupling) and HOPS (fusion). (khatter2015arflikegtpasearl8 pages 1-5, khatter2015arflikegtpasearl8 pages 8-10)
- Sharma et al. (2019; https://doi.org/10.16943/ptinsa/2019/49574) synthesize the evidence that ARL8 paralogs localize to lysosomes (not mitotic spindle) and function in BORC-dependent positioning and fusion programs, integrating immune-cell and disease-relevant contexts. (sharma2019emergingrolesof pages 10-11)

7) Statistics and quantitative data highlights (from included studies)

Prostate cancer survival association (ARL8A): HR 1.927 (95% CI 0.6692–5.547); log-rank P = 0.1471 (Kaplan–Meier plot); cohort example noted as Glinsky cohort n=79 in the figure caption context. (nturubika2024alteredexpressionof pages 5-5, nturubika2024alteredexpressionof media 25d4e50c)
Kinesin perturbation phenotype in lysosome distribution: KIF5B or KIF1B knockdown caused lysosome clustering in ~40% and ~85% of cells, respectively (HeLa). (guardia2016borcfunctionsupstream pages 4-5)
Human neurogenetics upstream of ARL8A: five affected children with biallelic BORCS8 variants; cellular rescue assays show patient alleles reduce ability to restore peripheral lysosome distribution and affect LC3B marker levels in BORCS8-KO cells. (pace2024biallelicborcs8variants pages 1-2, pace2024biallelicborcs8variants pages 11-12)

8) Functional summary (what ARL8A “does”)

Primary molecular function: ARL8A is a small lysosome-associated GTPase that, when in its active state and localized to lysosomal membranes, recruits effector proteins that couple lysosomes/endolysosomes to microtubule motors (kinesin-1 via SKIP/PLEKHM2; kinesin-3 via ARL8-dependent coupling) and coordinates lysosomal fusion competence via tethering machinery (HOPS-related pathways). This enables spatial organization of lysosomes and efficient trafficking/fusion with endocytic and autophagic carriers, with downstream impacts on degradative flux, cholesterol handling, and extracellular vesicle release. (rizalar2022investigationofbiogenesis pages 30-33, guardia2016borcfunctionsupstream pages 5-6, anderson2022borcarl8hopsensembleis pages 1-2, shelke2023inhibitionofendolysosome pages 1-2)

Cellular localization: cytosolic-facing lysosomal membrane association mediated by N-terminal amphipathic helix and acetylation. (khatter2015arflikegtpasearl8 pages 5-8, rizalar2022investigationofbiogenesis pages 30-33)

Pathways: BORC→ARL8→(SKIP/KLC2/KIF5B and KIF1A/KIF1Bβ) for positioning; ARL8→HOPS for fusion; BORC/ARL8/HOPS→NPC2 trafficking for cholesterol egress; BORC/ARL8/HOPS perturbation→exosome secretion increase; ARL8B (family)→DENND6A→Rab34→RILP/dynein for retrograde repositioning/autophagy coupling. (guardia2016borcfunctionsupstream pages 5-6, anderson2022borcarl8hopsensembleis pages 1-2, shelke2023inhibitionofendolysosome pages 1-2, kumar2024dennd6alinksarl8b pages 12-13)

Embedded summary artifact

Aspect	Key findings (1-2 sentences)	Evidence type (review/primary; cell line/animal/human cohort)	Key molecules/complexes	Representative sources with year+DOI/URL	Notes on ARL8A vs ARL8B specificity
Definition	ARL8A is the human ADP-ribosylation factor-like protein 8A, a small Arf-family GTPase and one of two vertebrate ARL8 paralogs; ARL8A and ARL8B are ~91% identical and share the core role of regulating lysosome dynamics. Family reviews place ARL8 proteins at the center of lysosomal positioning, trafficking, and fusion control. (rizalar2022investigationofbiogenesis pages 30-33, khatter2015arflikegtpasearl8 pages 5-8, khatter2015arflikegtpasearl8 pages 1-5)	Review plus family-level experimental summary; mammalian cell biology	ARL8A/ARL8B, Arf family small GTPases	Khatter et al., 2015, doi:10.1080/21592799.2015.1086501, https://doi.org/10.1080/21592799.2015.1086501; Rizalar, 2022, doi:10.17169/refubium-36173, https://doi.org/10.17169/refubium-36173	Much of the direct mechanistic literature is stronger for ARL8B, but family sources explicitly include ARL8A as the closely related human paralog.
Localization	ARL8A/ARL8B localize predominantly to lysosomes, showing high co-localization with lysosomal markers such as CD63 and LAMP2 rather than early endosome marker EEA1. Membrane association depends on an N-terminal amphipathic helix and N-terminal acetylation rather than canonical Arf myristoylation. (rizalar2022investigationofbiogenesis pages 30-33, khatter2015arflikegtpasearl8 pages 5-8)	Review and experimental localization studies; mammalian cells	Lysosome, CD63, LAMP2, amphipathic helix, NatC-mediated acetylation	Khatter et al., 2015, doi:10.1080/21592799.2015.1086501, https://doi.org/10.1080/21592799.2015.1086501; Rizalar, 2022, doi:10.17169/refubium-36173, https://doi.org/10.17169/refubium-36173	Evidence explicitly names both ARL8A and ARL8B for lysosomal localization; acetylation data are best established for ARL8B but are generally discussed at the ARL8-family level.
Upstream recruitment to lysosomes	BORC acts upstream of ARL8 proteins and is required for ARL8A/ARL8B recruitment to lysosomes; BORC loss causes juxtanuclear lysosome clustering and prevents normal centrifugal dispersal. Forced kinesin attachment can bypass BORC deficiency, supporting a motor-recruitment role upstream of transport. (khatter2015arflikegtpasearl8 pages 5-8, guardia2016borcfunctionsupstream pages 1-3, guardia2016borcfunctionsupstream pages 5-6, guardia2016borcfunctionsupstream pages 6-7)	Primary mechanistic studies in HeLa cells; review support	BORC, myrlysin/BORCS5, diaskedin, ARL8A/ARL8B	Guardia et al., 2016, doi:10.1016/j.celrep.2016.10.062, https://doi.org/10.1016/j.celrep.2016.10.062; Khatter et al., 2015, doi:10.1080/21592799.2015.1086501, https://doi.org/10.1080/21592799.2015.1086501	Guardia et al. directly tested Arl8a/Arl8b together in motor-dependence experiments; older reviews often emphasize ARL8B as the best-characterized paralog.
Anterograde lysosome motility	In the GTP-bound state, ARL8 recruits SKIP/PLEKHM2, which binds kinesin light chain KLC2 and enables kinesin-1-dependent plus-end transport of lysosomes toward the cell periphery. Overexpression of ARL8 proteins or SKIP promotes peripheral lysosome redistribution, whereas depletion causes perinuclear clustering. (rizalar2022investigationofbiogenesis pages 30-33, khatter2015arflikegtpasearl8 pages 8-10, guardia2016borcfunctionsupstream pages 5-6, guardia2016borcfunctionsupstream pages 4-5)	Primary cell-line studies plus reviews; mammalian cells	SKIP/PLEKHM2, KLC2, kinesin-1/KIF5B	Guardia et al., 2016, doi:10.1016/j.celrep.2016.10.062, https://doi.org/10.1016/j.celrep.2016.10.062; Khatter et al., 2015, doi:10.1080/21592799.2015.1086501, https://doi.org/10.1080/21592799.2015.1086501	Core mechanism is usually demonstrated with ARL8B, but family evidence and knockdown/KO logic indicate ARL8A contributes and can overlap functionally with ARL8B.
Kinesin-3 and track-specific transport	BORC-ARL8 functions upstream of kinesin-3 as well as kinesin-1; KIF1A/KIF1Bβ drive lysosome movement on more peripheral, tyrosinated microtubules, whereas KIF5B favors more central, acetylated microtubules. This establishes regional routing of lysosomes along different microtubule tracks. (shelke2023inhibitionofendolysosome pages 1-2, guardia2016borcfunctionsupstream pages 1-3, guardia2016borcfunctionsupstream pages 10-11, guardia2016borcfunctionsupstream pages 7-10)	Primary mechanistic cell-line studies	KIF1A, KIF1Bβ, KIF5B, acetylated vs tyrosinated microtubules, BORC-ARL8	Guardia et al., 2016, doi:10.1016/j.celrep.2016.10.062, https://doi.org/10.1016/j.celrep.2016.10.062; Shelke et al., 2023, doi:10.1083/jcb.202209084, https://doi.org/10.1083/jcb.202209084	Direct kinesin-3 binding is commonly described for ARL8 family members; the literature usually does not isolate ARL8A-specific biochemistry from ARL8B here.
Retrograde positioning / bidirectional control	Although ARL8 is best known for outward movement, newer work shows it also participates in retrograde programs through effectors such as RUFY3/RUFY4 and DENND6A-Rab34-RILP-dynein, helping reposition lysosomes toward the juxtanuclear region under specific conditions. This reframes ARL8 as a bidirectional organizer rather than a purely anterograde factor. (kumar2024dennd6alinksarl8b pages 12-13, shelke2023inhibitionofendolysosome pages 1-2)	Primary mechanistic studies; mammalian cells	RUFY3, RUFY4, DENND6A, Rab34, RILP, dynein-dynactin	Kumar et al., 2024, doi:10.1038/s41467-024-44957-1, https://doi.org/10.1038/s41467-024-44957-1; Shelke et al., 2023, doi:10.1083/jcb.202209084, https://doi.org/10.1083/jcb.202209084	Recent retrograde work is mostly centered on ARL8B or combined ARL8A/ARL8B depletion; ARL8A-specific contribution remains less resolved.
Fusion and degradative trafficking	ARL8 recruits HOPS-related machinery to lysosomes and promotes fusion of lysosomes with late endosomes and autophagic cargo carriers, supporting degradative trafficking. Disrupting ARL8-HOPS function impairs endolysosomal fusion and cargo degradation. (sharma2019emergingrolesof pages 11-13, khatter2015arflikegtpasearl8 pages 8-10, khatter2015arflikegtpasearl8 pages 1-5, anderson2022borcarl8hopsensembleis pages 1-2)	Review plus primary cellular studies	HOPS, VPS41, VPS39, PLEKHM1, late endosomes, autophagosomes	Marwaha et al., 2017, doi:10.1083/jcb.201607085, https://doi.org/10.1083/jcb.201607085; Anderson et al., 2022, doi:10.1091/mbc.e21-11-0595-t, https://doi.org/10.1091/mbc.e21-11-0595-t; Khatter et al., 2015, doi:10.1080/21592799.2015.1086501, https://doi.org/10.1080/21592799.2015.1086501	Direct binding/fusion studies are largely ARL8B-focused; ARL8A is inferred as a paralog with overlapping lysosomal functions unless otherwise specified.
Cholesterol egress pathway	The BORC-ARL8-HOPS ensemble is required for lysosomal cholesterol egress by enabling proper NPC2 delivery/retention in the endolysosomal system and supporting CI-MPR-dependent trafficking. Loss of BORC, ARL8, or HOPS leads to cholesterol accumulation in lysosomes and increased NPC2 secretion. (anderson2022borcarl8hopsensembleis pages 1-2)	Primary cell-line study with trafficking assays	BORC, ARL8, HOPS, NPC2, CI-MPR, lysosomal cholesterol	Anderson et al., 2022, doi:10.1091/mbc.e21-11-0595-t, https://doi.org/10.1091/mbc.e21-11-0595-t	Study examines ARL8 in a pathway context rather than isolating ARL8A alone; evidence supports ARL8-family relevance to cholesterol homeostasis.
Exosome secretion	Inhibition of BORC-ARL8-HOPS-dependent endolysosome fusion increases exosome secretion because multivesicular endosomes are less able to fuse with lysosomes and instead remain available for extracellular vesicle release. HeLa ARL8A/ARL8B double-KO cells were used in this mechanistic framework. (shelke2023inhibitionofendolysosome pages 1-2)	Primary cell-line study; HeLa KO models	BORC, ARL8A/ARL8B, HOPS, MVEs, exosomes	Shelke et al., 2023, doi:10.1083/jcb.202209084, https://doi.org/10.1083/jcb.202209084	This is one of the clearer recent settings where ARL8A/ARL8B are explicitly studied together via double knockout rather than ARL8B alone.
Autophagy	ARL8-dependent positioning intersects with autophagy: nutrient or pH shifts alter ARL8-associated lysosome localization, and perturbing ARL8-linked pathways can affect autophagic flux and LC3B accumulation. BORCS8 disease alleles that impair the BORC-ARL8 axis also cause lysosome clustering and LC3B accumulation, consistent with defective lysosome-autophagosome fusion. (khatter2015arflikegtpasearl8 pages 8-10, kumar2024dennd6alinksarl8b pages 12-13, pace2024biallelicborcs8variants pages 15-16, pace2024biallelicborcs8variants pages 11-12)	Reviews plus primary cell-line and disease-model studies	LC3B, BORC, DENND6A, lysosome-autophagosome fusion	Kumar et al., 2024, doi:10.1038/s41467-024-44957-1, https://doi.org/10.1038/s41467-024-44957-1; De Pace et al., 2024, doi:10.1093/brain/awad427, https://doi.org/10.1093/brain/awad427	ARL8A-specific autophagy evidence is limited; most current evidence supports an ARL8-family role or uses BORC perturbation upstream of ARL8A/ARL8B.
Immune and specialized cell functions	ARL8-family lysosomal transport influences antigen presentation and specialized lysosome-related organelle positioning, including lysosome tubulation in macrophages/dendritic cells and trafficking relevant to CD1d/MHC II presentation. More recent phagocyte work links ARL8-positive endolysosome positioning to immune activation programs, although that literature is centered on ARL8B-positive compartments. (khatter2015arflikegtpasearl8 pages 8-10, sharma2019emergingrolesof pages 10-11)	Review and immune-cell primary studies	CD1d, MHC II, lytic granules, macrophage lysosome tubules	Khatter et al., 2015, doi:10.1080/21592799.2015.1086501, https://doi.org/10.1080/21592799.2015.1086501; Sharma et al., 2019, doi:10.16943/ptinsa/2019/49574, https://doi.org/10.16943/ptinsa/2019/49574	Direct immune-function studies overwhelmingly emphasize ARL8B; ARL8A is usually implicated by paralogy rather than direct assay.
Neuronal / axonal relevance	ARL8-family proteins participate in long-range neuronal transport, and BORC-dependent recruitment of ARL8 and kinesins is important for distal axon lysosome transport. Human and zebrafish BORCS8 disease data underscore the importance of this pathway for CNS development and function. (rizalar2022investigationofbiogenesis pages 30-33, pace2024biallelicborcs8variants pages 1-2, pace2024biallelicborcs8variants pages 16-17, pace2024biallelicborcs8variants pages 11-12)	Experimental neurobiology and human genetics; animal models and human families	BORC, ARL8, kinesin-1, kinesin-3, distal axon lysosomes	De Pace et al., 2024, doi:10.1093/brain/awad427, https://doi.org/10.1093/brain/awad427; Rizalar, 2022, doi:10.17169/refubium-36173, https://doi.org/10.17169/refubium-36173	Pathway-level evidence is strong, but ARL8A-specific neuronal assays in human remain sparse relative to ARL8-family or BORC-level evidence.
Human disease association	No monogenic human disease is established here for ARL8A itself, but ARL8 pathway disruption is disease-relevant: biallelic BORCS8 variants in five children caused severe infantile-onset neurodegenerative disease with impaired lysosome dispersal, and prostate cancer datasets showed a non-significant ARL8A survival trend. These data support translational relevance of the pathway more strongly than ARL8A as a standalone disease gene. (nturubika2024alteredexpressionof pages 5-5, pace2024biallelicborcs8variants pages 1-2, pace2024biallelicborcs8variants pages 12-13, nturubika2024alteredexpressionof media 25d4e50c)	Human cohort/genetics plus cell validation	BORCS8, ARL8 pathway, prostate cancer cohorts	De Pace et al., 2024, doi:10.1093/brain/awad427, https://doi.org/10.1093/brain/awad427; Nturubika et al., 2024, doi:10.1038/s41416-024-02829-x, https://doi.org/10.1038/s41416-024-02829-x	ARL8A-specific human association in prostate cancer was not statistically significant: log-rank P=0.1471, HR 1.927 (95% CI 0.6692-5.547); disease evidence is stronger for upstream BORC genes than for ARL8A itself.
Applications / real-world implementation	Current applications are mainly mechanistic and translational rather than clinical: ARL8 pathway components are used experimentally to manipulate lysosome positioning, degradative flux, cholesterol handling, and exosome release. In cancer and neurodegeneration research, this pathway is being studied as a systems-level vulnerability rather than as an established ARL8A-targeted therapy. (shelke2023inhibitionofendolysosome pages 1-2, kumar2024dennd6alinksarl8b pages 12-13, anderson2022borcarl8hopsensembleis pages 1-2, nturubika2024alteredexpressionof pages 5-5)	Primary research applications in cell biology, cancer biology, and neurobiology	Exosomes, cholesterol trafficking, autophagy, lysosome positioning	Shelke et al., 2023, doi:10.1083/jcb.202209084, https://doi.org/10.1083/jcb.202209084; Kumar et al., 2024, doi:10.1038/s41467-024-44957-1, https://doi.org/10.1038/s41467-024-44957-1; Anderson et al., 2022, doi:10.1091/mbc.e21-11-0595-t, https://doi.org/10.1091/mbc.e21-11-0595-t	There is no evidence in the gathered set for an approved ARL8A-directed diagnostic or therapy; implementations are presently research-use and pathway-oriented.

Table: This table summarizes the strongest gathered evidence for human ARL8A functional annotation, emphasizing where evidence is direct for ARL8A versus inferred from the closely related paralog ARL8B or shared ARL8-family studies.

Figure evidence (example quantitative association)

A cropped Kaplan–Meier panel for ARL8A from Nturubika et al. 2024 is available and shows Log-rank P = 0.1471 and HR = 1.927 (0.6692–5.547). (nturubika2024alteredexpressionof media 25d4e50c)

Limitations of the current evidence set

Many high-resolution mechanistic studies prioritize ARL8B, and ARL8A-specific biochemistry (distinct GEFs/GAPs, unique effectors, tissue-specific non-redundant roles) is not strongly resolved in the retrieved texts; therefore, some ARL8A conclusions are paralog-inferred based on ARL8-family experiments and double-KD/double-KO logic. (khatter2015arflikegtpasearl8 pages 5-8, guardia2016borcfunctionsupstream pages 5-6, kumar2024dennd6alinksarl8b pages 12-13)
Some quantitative details for BORCS8 patient-variant cellular assays (exact peripheral LAMP1 percentages) were described as analyzed but not numerically present in the excerpted text segments available here. (pace2024biallelicborcs8variants pages 12-13, pace2024biallelicborcs8variants pages 4-5)

References

(rizalar2022investigationofbiogenesis pages 30-33): Filiz Sila Rizalar. Investigation of biogenesis of the presynaptic compartments using human ipsc-derived neurons. Text, Jan 2022. URL: https://doi.org/10.17169/refubium-36173, doi:10.17169/refubium-36173. This article has 0 citations and is from a peer-reviewed journal.
(khatter2015arflikegtpasearl8 pages 5-8): Divya Khatter, Aastha Sindhwani, and Mahak Sharma. Arf-like gtpase arl8: moving from the periphery to the center of lysosomal biology. Cellular Logistics, 5:e1086501, Jul 2015. URL: https://doi.org/10.1080/21592799.2015.1086501, doi:10.1080/21592799.2015.1086501. This article has 111 citations.
(shelke2023inhibitionofendolysosome pages 1-2): Ganesh Vilas Shelke, Chad D. Williamson, Michal Jarnik, and Juan S. Bonifacino. Inhibition of endolysosome fusion increases exosome secretion. The Journal of Cell Biology, May 2023. URL: https://doi.org/10.1083/jcb.202209084, doi:10.1083/jcb.202209084. This article has 57 citations.
(guardia2016borcfunctionsupstream pages 5-6): Carlos M. Guardia, Ginny G. Farías, Rui Jia, Jing Pu, and Juan S. Bonifacino. Borc functions upstream of kinesins 1 and 3 to coordinate regional movement of lysosomes along different microtubule tracks. Cell reports, 17 8:1950-1961, Nov 2016. URL: https://doi.org/10.1016/j.celrep.2016.10.062, doi:10.1016/j.celrep.2016.10.062. This article has 307 citations and is from a highest quality peer-reviewed journal.
(khatter2015arflikegtpasearl8 pages 8-10): Divya Khatter, Aastha Sindhwani, and Mahak Sharma. Arf-like gtpase arl8: moving from the periphery to the center of lysosomal biology. Cellular Logistics, 5:e1086501, Jul 2015. URL: https://doi.org/10.1080/21592799.2015.1086501, doi:10.1080/21592799.2015.1086501. This article has 111 citations.
(guardia2016borcfunctionsupstream pages 1-3): Carlos M. Guardia, Ginny G. Farías, Rui Jia, Jing Pu, and Juan S. Bonifacino. Borc functions upstream of kinesins 1 and 3 to coordinate regional movement of lysosomes along different microtubule tracks. Cell reports, 17 8:1950-1961, Nov 2016. URL: https://doi.org/10.1016/j.celrep.2016.10.062, doi:10.1016/j.celrep.2016.10.062. This article has 307 citations and is from a highest quality peer-reviewed journal.
(guardia2016borcfunctionsupstream pages 4-5): Carlos M. Guardia, Ginny G. Farías, Rui Jia, Jing Pu, and Juan S. Bonifacino. Borc functions upstream of kinesins 1 and 3 to coordinate regional movement of lysosomes along different microtubule tracks. Cell reports, 17 8:1950-1961, Nov 2016. URL: https://doi.org/10.1016/j.celrep.2016.10.062, doi:10.1016/j.celrep.2016.10.062. This article has 307 citations and is from a highest quality peer-reviewed journal.
(guardia2016borcfunctionsupstream pages 10-11): Carlos M. Guardia, Ginny G. Farías, Rui Jia, Jing Pu, and Juan S. Bonifacino. Borc functions upstream of kinesins 1 and 3 to coordinate regional movement of lysosomes along different microtubule tracks. Cell reports, 17 8:1950-1961, Nov 2016. URL: https://doi.org/10.1016/j.celrep.2016.10.062, doi:10.1016/j.celrep.2016.10.062. This article has 307 citations and is from a highest quality peer-reviewed journal.
(sharma2019emergingrolesof pages 10-11): Emerging Roles of Arf-Like GTP-Binding Proteins: From Membrane Trafficking to Cytoskeleton Dynamics and Beyond This article has 11 citations.
(anderson2022borcarl8hopsensembleis pages 1-2): Jacob Anderson, Gerard Walker, and Jing Pu. Borc-arl8-hops ensemble is required for lysosomal cholesterol egress through npc2. Aug 2022. URL: https://doi.org/10.1091/mbc.e21-11-0595-t, doi:10.1091/mbc.e21-11-0595-t. This article has 22 citations and is from a domain leading peer-reviewed journal.
(kumar2024dennd6alinksarl8b pages 12-13): Rahul Kumar, Maleeha Khan, Vincent Francis, Adriana Aguila, Gopinath Kulasekaran, Emily Banks, and Peter S. McPherson. Dennd6a links arl8b to a rab34/rilp/dynein complex, regulating lysosomal positioning and autophagy. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-024-44957-1, doi:10.1038/s41467-024-44957-1. This article has 27 citations and is from a highest quality peer-reviewed journal.
(pace2024biallelicborcs8variants pages 1-2): Raffaella De Pace, Reza Maroofian, Adeline Paimboeuf, Mina Zamani, Maha S Zaki, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Jawaher Zeighami, Chad D Williamson, Emily Fleming, Dihong Zhou, Jennifer L Gannon, Isabelle Thiffault, Emmanuel Roze, Mohnish Suri, Giovanni Zifarelli, Peter Bauer, Henry Houlden, Mariasavina Severino, Shunmoogum A Patten, Emily Farrow, and Juan S Bonifacino. Biallelic borcs8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics. Brain : a journal of neurology, 147:1751-1767, Dec 2024. URL: https://doi.org/10.1093/brain/awad427, doi:10.1093/brain/awad427. This article has 24 citations.
(pace2024biallelicborcs8variants pages 15-16): Raffaella De Pace, Reza Maroofian, Adeline Paimboeuf, Mina Zamani, Maha S Zaki, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Jawaher Zeighami, Chad D Williamson, Emily Fleming, Dihong Zhou, Jennifer L Gannon, Isabelle Thiffault, Emmanuel Roze, Mohnish Suri, Giovanni Zifarelli, Peter Bauer, Henry Houlden, Mariasavina Severino, Shunmoogum A Patten, Emily Farrow, and Juan S Bonifacino. Biallelic borcs8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics. Brain : a journal of neurology, 147:1751-1767, Dec 2024. URL: https://doi.org/10.1093/brain/awad427, doi:10.1093/brain/awad427. This article has 24 citations.
(nturubika2024alteredexpressionof pages 5-5): Bukuru D. Nturubika, Carlos M. Guardia, David C. Gershlick, Jessica M. Logan, Carmela Martini, Jessica K. Heatlie, Joanna Lazniewska, Courtney Moore, Giang T. Lam, Ka L. Li, Ben S-Y Ung, Robert D. Brooks, Shane M. Hickey, Andrew G. Bert, Philip A. Gregory, Lisa M. Butler, John J. O’Leary, Douglas A. Brooks, and Ian R. D. Johnson. Altered expression of vesicular trafficking machinery in prostate cancer affects lysosomal dynamics and provides insight into the underlying biology and disease progression. British Journal of Cancer, 131:1263-1278, Aug 2024. URL: https://doi.org/10.1038/s41416-024-02829-x, doi:10.1038/s41416-024-02829-x. This article has 10 citations and is from a domain leading peer-reviewed journal.
(nturubika2024alteredexpressionof media 25d4e50c): Bukuru D. Nturubika, Carlos M. Guardia, David C. Gershlick, Jessica M. Logan, Carmela Martini, Jessica K. Heatlie, Joanna Lazniewska, Courtney Moore, Giang T. Lam, Ka L. Li, Ben S-Y Ung, Robert D. Brooks, Shane M. Hickey, Andrew G. Bert, Philip A. Gregory, Lisa M. Butler, John J. O’Leary, Douglas A. Brooks, and Ian R. D. Johnson. Altered expression of vesicular trafficking machinery in prostate cancer affects lysosomal dynamics and provides insight into the underlying biology and disease progression. British Journal of Cancer, 131:1263-1278, Aug 2024. URL: https://doi.org/10.1038/s41416-024-02829-x, doi:10.1038/s41416-024-02829-x. This article has 10 citations and is from a domain leading peer-reviewed journal.
(khatter2015arflikegtpasearl8 pages 1-5): Divya Khatter, Aastha Sindhwani, and Mahak Sharma. Arf-like gtpase arl8: moving from the periphery to the center of lysosomal biology. Cellular Logistics, 5:e1086501, Jul 2015. URL: https://doi.org/10.1080/21592799.2015.1086501, doi:10.1080/21592799.2015.1086501. This article has 111 citations.
(pace2024biallelicborcs8variants pages 11-12): Raffaella De Pace, Reza Maroofian, Adeline Paimboeuf, Mina Zamani, Maha S Zaki, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Jawaher Zeighami, Chad D Williamson, Emily Fleming, Dihong Zhou, Jennifer L Gannon, Isabelle Thiffault, Emmanuel Roze, Mohnish Suri, Giovanni Zifarelli, Peter Bauer, Henry Houlden, Mariasavina Severino, Shunmoogum A Patten, Emily Farrow, and Juan S Bonifacino. Biallelic borcs8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics. Brain : a journal of neurology, 147:1751-1767, Dec 2024. URL: https://doi.org/10.1093/brain/awad427, doi:10.1093/brain/awad427. This article has 24 citations.
(guardia2016borcfunctionsupstream pages 6-7): Carlos M. Guardia, Ginny G. Farías, Rui Jia, Jing Pu, and Juan S. Bonifacino. Borc functions upstream of kinesins 1 and 3 to coordinate regional movement of lysosomes along different microtubule tracks. Cell reports, 17 8:1950-1961, Nov 2016. URL: https://doi.org/10.1016/j.celrep.2016.10.062, doi:10.1016/j.celrep.2016.10.062. This article has 307 citations and is from a highest quality peer-reviewed journal.
(guardia2016borcfunctionsupstream pages 7-10): Carlos M. Guardia, Ginny G. Farías, Rui Jia, Jing Pu, and Juan S. Bonifacino. Borc functions upstream of kinesins 1 and 3 to coordinate regional movement of lysosomes along different microtubule tracks. Cell reports, 17 8:1950-1961, Nov 2016. URL: https://doi.org/10.1016/j.celrep.2016.10.062, doi:10.1016/j.celrep.2016.10.062. This article has 307 citations and is from a highest quality peer-reviewed journal.
(sharma2019emergingrolesof pages 11-13): Emerging Roles of Arf-Like GTP-Binding Proteins: From Membrane Trafficking to Cytoskeleton Dynamics and Beyond This article has 11 citations.
(pace2024biallelicborcs8variants pages 16-17): Raffaella De Pace, Reza Maroofian, Adeline Paimboeuf, Mina Zamani, Maha S Zaki, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Jawaher Zeighami, Chad D Williamson, Emily Fleming, Dihong Zhou, Jennifer L Gannon, Isabelle Thiffault, Emmanuel Roze, Mohnish Suri, Giovanni Zifarelli, Peter Bauer, Henry Houlden, Mariasavina Severino, Shunmoogum A Patten, Emily Farrow, and Juan S Bonifacino. Biallelic borcs8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics. Brain : a journal of neurology, 147:1751-1767, Dec 2024. URL: https://doi.org/10.1093/brain/awad427, doi:10.1093/brain/awad427. This article has 24 citations.
(pace2024biallelicborcs8variants pages 12-13): Raffaella De Pace, Reza Maroofian, Adeline Paimboeuf, Mina Zamani, Maha S Zaki, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Jawaher Zeighami, Chad D Williamson, Emily Fleming, Dihong Zhou, Jennifer L Gannon, Isabelle Thiffault, Emmanuel Roze, Mohnish Suri, Giovanni Zifarelli, Peter Bauer, Henry Houlden, Mariasavina Severino, Shunmoogum A Patten, Emily Farrow, and Juan S Bonifacino. Biallelic borcs8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics. Brain : a journal of neurology, 147:1751-1767, Dec 2024. URL: https://doi.org/10.1093/brain/awad427, doi:10.1093/brain/awad427. This article has 24 citations.
(pace2024biallelicborcs8variants pages 4-5): Raffaella De Pace, Reza Maroofian, Adeline Paimboeuf, Mina Zamani, Maha S Zaki, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Jawaher Zeighami, Chad D Williamson, Emily Fleming, Dihong Zhou, Jennifer L Gannon, Isabelle Thiffault, Emmanuel Roze, Mohnish Suri, Giovanni Zifarelli, Peter Bauer, Henry Houlden, Mariasavina Severino, Shunmoogum A Patten, Emily Farrow, and Juan S Bonifacino. Biallelic borcs8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics. Brain : a journal of neurology, 147:1751-1767, Dec 2024. URL: https://doi.org/10.1093/brain/awad427, doi:10.1093/brain/awad427. This article has 24 citations.

Artifacts

Edison artifact artifact-00

Citations

rizalar2022investigationofbiogenesis pages 30-33
guardia2016borcfunctionsupstream pages 5-6
guardia2016borcfunctionsupstream pages 4-5
shelke2023inhibitionofendolysosome pages 1-2
sharma2019emergingrolesof pages 10-11
guardia2016borcfunctionsupstream pages 1-3
guardia2016borcfunctionsupstream pages 10-11
nturubika2024alteredexpressionof pages 5-5
guardia2016borcfunctionsupstream pages 6-7
guardia2016borcfunctionsupstream pages 7-10
sharma2019emergingrolesof pages 11-13
https://doi.org/10.1016/j.celrep.2016.10.062
https://doi.org/10.1083/jcb.202209084
https://doi.org/10.1091/mbc.e21-11-0595-t
https://doi.org/10.1038/s41467-024-44957-1
https://doi.org/10.1093/brain/awad427
https://doi.org/10.1038/s41416-024-02829-x
https://doi.org/10.1080/21592799.2015.1086501
https://doi.org/10.16943/ptinsa/2019/49574
https://doi.org/10.1080/21592799.2015.1086501;
https://doi.org/10.17169/refubium-36173
https://doi.org/10.1016/j.celrep.2016.10.062;
https://doi.org/10.1038/s41467-024-44957-1;
https://doi.org/10.1083/jcb.201607085;
https://doi.org/10.1091/mbc.e21-11-0595-t;
https://doi.org/10.1093/brain/awad427;
https://doi.org/10.1083/jcb.202209084;
https://doi.org/10.17169/refubium-36173,
https://doi.org/10.1080/21592799.2015.1086501,
https://doi.org/10.1083/jcb.202209084,
https://doi.org/10.1016/j.celrep.2016.10.062,
https://doi.org/10.1091/mbc.e21-11-0595-t,
https://doi.org/10.1038/s41467-024-44957-1,
https://doi.org/10.1093/brain/awad427,
https://doi.org/10.1038/s41416-024-02829-x,

📚 Additional Documentation

Notes

(ARL8A-notes.md)

ARL8A review notes

Deep research provider status

Falcon deep research was attempted for the PN batch review, but the provider timed out after 600 seconds. The configured perplexity-lite fallback was then attempted and failed with a 401 quota error, so no ARL8A-deep-research-falcon.md or fallback provider output was produced. This review therefore uses the fetched UniProt/GOA records, cached PMID texts, Reactome cache, and PN projection/audit reports.

Evidence summary

ARL8A encodes one of the two mammalian ARL8 small GTPases. The clearest direct experimental result is that ARL8A and ARL8B localize to lysosomes and affect lysosome motility: Hofmann and Munro report that "Arl8a and Arl8b ... localise to lysosomes in mammalian cells" and that overexpression redistributes lysosomes toward the cell periphery in a microtubule-dependent manner PMID:16537643. The original GIE/ARL8 paper also supports GTP binding, tubulin association, spindle-midzone localization, and a chromosome-segregation phenotype, but this is a secondary mitotic context for the PN review rather than the proteostasis-centered function PMID:15331635.

The BORC paper places ARL8 in lysosome positioning: BORC recruits Arl8 to lysosomes and initiates kinesin-dependent movement toward microtubule plus ends PMID:25898167. PLEKHM1/HOPS and RUFY3/RUFY4 papers expand this into a broader endolysosomal transport/fusion network. PLEKHM1 binds Arl8b and promotes delivery/degradation of endocytic and autophagic cargo in lysosomes PMID:28325809. RUFY3/RUFY4 are ARL8 effectors that couple endolysosomes to dynein-dynactin for retrograde microtubule transport PMID:35314674.

PN projection decision

The PN projection file proposes ARL8A as a candidate new annotation to GO:0061906 autophagosome localization from the Autophagy-Lysosome Pathway / Localization of the autophagosome / Movement of autophagosomes along microtubules / HOPS-BORC complex bridging path. The mapping audit marks this projection family as requiring manual gene-level review before changing a gene review. For ARL8A, the strongest direct evidence supports lysosome/endolysosome localization and transport. The available ARL8 autophagy evidence is mostly about lysosome positioning, HOPS recruitment, and delivery or degradation of autophagic cargo in lysosomes, not direct ARL8A-dependent positioning of autophagosomes themselves. Therefore this review does not add GO:0061906 for ARL8A; it records the projection as an expert question/experimental follow-up.

Falcon deep research findings (2026-06-07)

A Falcon (Edison) deep research report was generated and is now available (ARL8A-deep-research-falcon.md); it supersedes the earlier "provider timed out" status above. The report adds several primary references absent from the prior review. PMIDs below were resolved via PubMed. Most ARL8A-specific conclusions remain paralog-inferred from ARL8B / shared ARL8-family or double-KD/double-KO experiments, which I label explicitly.

CONFIRMS (with new direct ARL8A evidence): BORC functions upstream of ARL8 to drive kinesin-dependent peripheral lysosome dispersal, coupling to both kinesin-1 (KIF5B) and kinesin-3 (KIF1A/KIF1Bbeta) on distinct microtubule tracks (KIF5B on central acetylated tracks; KIF1A/KIF1Bbeta on peripheral tyrosinated tracks). Notably, in an ARL8B-knockout background, siRNA against ARL8A removes the residual ability of kinesin constructs to disperse lysosomes — direct evidence that ARL8A itself contributes to the transport program, not just ARL8B [PMID:27851960 Guardia 2016 "BORC Functions Upstream of Kinesins 1 and 3..."]. This strengthens the existing lysosome-localization / anterograde-transport annotations.
NEW (pathway / process): The BORC-ARL8-HOPS ensemble is required for lysosomal free-cholesterol egress via NPC2; depletion of BORC, ARL8, or HOPS causes lysosomal free-cholesterol accumulation, reduced NPC2 retention with increased NPC2 secretion, and increased lysosomal degradation of CI-MPR [PMID:35653304 Anderson 2022 "BORC-ARL8-HOPS ensemble is required for lysosomal cholesterol egress through NPC2"]. Pathway-level (ARL8 family), not ARL8A-specific.
NEW (process), with strong ARL8A relevance: Disruption of BORC-ARL8-HOPS-dependent endolysosome fusion increases exosome secretion (multivesicular endosomes fail to fuse with lysosomes, so intraluminal vesicles are released extracellularly). This study used HeLa ARL8A/ARL8B double-knockout models, making it one of the clearer settings where ARL8A is explicitly perturbed alongside ARL8B [PMID:37213076 Shelke 2023 "Inhibition of endolysosome fusion increases exosome secretion"]. This is mechanistically relevant context for the existing extracellular-exosome annotation (which remains MARK_AS_OVER_ANNOTATED as a steady-state location; the new data concern a functional fusion role, not ARL8A residing in exosomes).
NEW (interactions/retrograde), ARL8B-centered: DENND6A is an ARL8B effector that activates Rab34, recruiting a RILP/dynein-dynactin complex to drive retrograde (juxtanuclear) lysosome transport and supporting autophagic flux; double knockdown of ARL8A and ARL8B reduces DENND6A localization phenotypes (ARL8-family requirement) [PMID:38296963 Kumar 2024 "DENND6A links Arl8b to a Rab34/RILP/dynein complex..."]. Complements the existing RUFY3/RUFY4 retrograde-coupling annotation (PMID:35314674).
NEW (disease, pathway-level/translational): Biallelic BORCS8 (a BORC subunit upstream of ARL8) variants cause a severe early-infantile neurodegenerative disorder in five children from three families; patient alleles impair BORC assembly and the ability to restore peripheral lysosome distribution, and zebrafish borcs8 knockout recapitulates brain/eye and locomotor phenotypes [PMID:38128568 De Pace 2024 "Biallelic BORCS8 variants cause an infantile-onset neurodegenerative disorder..."]. This is upstream of ARL8A, not a monogenic ARL8A disease, but validates the BORC->ARL8->kinesin axis physiologically in humans.
PROVISIONAL / low-confidence (do NOT use to change annotations): In prostate cancer cohorts, ARL8A expression showed only a non-significant survival association (log-rank P=0.1471, HR=1.927, 95% CI 0.6692-5.547) [PMID:39217195 Nturubika 2024 "Altered expression of vesicular trafficking machinery in prostate cancer..."]. Non-significant; recorded for completeness only.
CONFIRMS (localization mechanism): ARL8 proteins lack canonical Arf N-myristoylation; membrane targeting to lysosomes relies on an N-terminal amphipathic helix and N-terminal acetylation (NatC), consistent with the existing PMID:16537643-based localization (the original paper title itself is "An N-terminally acetylated Arf-like GTPase..."). Acetylation data are best established at the ARL8-family/ARL8B level [Khatter 2015 review doi:10.1080/21592799.2015.1086501; PMID:16537643].

Decision: I will add the six newly-resolved primary references (Guardia 2016, Anderson 2022, Shelke 2023, Kumar 2024, De Pace 2024, Nturubika 2024) to the review references: as statement-only findings (no supporting_text, since none of these are cached in /publications). I will not change any existing annotation action: none of the new evidence contradicts prior calls; rather it reinforces lysosome localization, anterograde/retrograde transport, and fusion-linked roles, and adds new pathway context (cholesterol egress, exosome secretion, BORC-disease axis). I add a couple of suggested questions/experiments for the cholesterol-egress and exosome roles.

Pn Notes

(ARL8A-pn-notes.md)

ARL8A PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q96BM9
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1368)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ARL8A/ARL8A-ai-review.yaml
AIGR review HTML: present - genes/human/ARL8A/ARL8A-ai-review.html
Gene notes: present - genes/human/ARL8A/ARL8A-notes.md
GOA TSV: present - genes/human/ARL8A/ARL8A-goa.tsv
UniProt record: present - genes/human/ARL8A/ARL8A-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ARL8A.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ARL8A.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/ARL8A/ARL8A-deep-research-falcon.md

AIGR Review Snapshot

Description: ARL8A encodes ADP-ribosylation factor-like protein 8A, an ARF-family small GTPase that associates with lysosomal and late-endosomal membranes in its active GTP-bound state. Together with ARL8B, it organizes endolysosome positioning and microtubule-based motility by engaging BORC-dependent recruitment and effectors such as SKIP/PLEKHM2, PLEKHM1/HOPS, and RUFY3/RUFY4. These interactions support peripheral and juxtanuclear redistribution of lysosomes/endolysosomes, cargo delivery to lysosomes, and specialized neuronal axonal transport of lysosome-related vesicles. ARL8A also has reported tubulin/spindle-midzone associations and chromosome-segregation phenotypes from early GIE studies, but those mitotic observations are secondary to its endolysosomal transport role.
Existing/core annotation action counts: ACCEPT: 10; KEEP_AS_NON_CORE: 15; MARK_AS_OVER_ANNOTATED: 1; MODIFY: 1; REMOVE: 12

PN Consistency Summary

Consistency: Consistent, with a deliberate PN-vs-review divergence (below). DR ↔ notes ↔ YAML agree: ARL8A is a lysosomal/endolysosomal small GTPase for lysosome positioning and BORC-kinesin/dynein-coupled transport; most ARL8A-specific conclusions are paralog-inferred from ARL8B but direct ARL8A contribution shown by ARL8B-KO + ARL8A-siRNA (PMID:27851960).
PN story / NEW pressure: PN's projected term GO:0061906 autophagosome localization (verified real, new_to_goa): review DECLINES. Evidence supports lysosome/endolysosome positioning and HOPS-mediated cargo delivery, not direct ARL8A-dependent positioning of autophagosomes as the transported organelle. Over-reaches as written. Review instead anchors on GO:0032418 lysosome localization. Conclude: GO:0061906 not yet supported for ARL8A; recorded as suggested question/experiment.
Evidence alignment: PN cites tandfonline/NatComms titles (Arl8 review; BORC; RUFY3/4 = PMID:35314674). Review/notes anchor on PMID:16537643 (ARL8a/b lysosome localization), 25898167 (BORC), 28325809 (PLEKHM1), 35314674 (RUFY3/4). DR added PMID:27851960, 35653304 (cholesterol egress), 37213076 (exosomes, ARL8A/B dKO), 38296963 (DENND6A), 38128568 (BORCS8 disease) statement-only. Strong overlap (RUFY3/4); review broader.
Verdict: Consistent; PN GO:0061906 over-reaches for ARL8A (lysosome vs autophagosome positioning); review correctly declines and uses GO:0032418.

Full Consistency Review

UniProt: Q96BM9 · batch: proteostasis-batch-2026-06-03 (Falcon DR 2026-06-07) · review status: COMPLETE
PN placement: 2 rows, ALP. (1) …Localization of the autophagosome|Movement of autophagosomes along microtubules|HOPS-BORC complex bridging; (2) …Autophagosome-lysosome docking|HOPS-BORC interaction mediator. PN-node mapping: localization group + movement/bridging leaves=mapped→GO:0061906 autophagosome localization (new_to_goa); docking nodes=context_only→GO:0061909; class=context_only→GO:0016236.
Consistency: Consistent, with a deliberate PN-vs-review divergence (below). DR ↔ notes ↔ YAML agree: ARL8A is a lysosomal/endolysosomal small GTPase for lysosome positioning and BORC-kinesin/dynein-coupled transport; most ARL8A-specific conclusions are paralog-inferred from ARL8B but direct ARL8A contribution shown by ARL8B-KO + ARL8A-siRNA (PMID:27851960).
PN story / NEW pressure: PN's projected term GO:0061906 autophagosome localization (verified real, new_to_goa): review DECLINES. Evidence supports lysosome/endolysosome positioning and HOPS-mediated cargo delivery, not direct ARL8A-dependent positioning of autophagosomes as the transported organelle. Over-reaches as written. Review instead anchors on GO:0032418 lysosome localization. Conclude: GO:0061906 not yet supported for ARL8A; recorded as suggested question/experiment.
Mapping strategy: Mapping flagged manual_gene_level_review_required; gene-level review here declines projection to ARL8A. The "autophagosome localization" leaf conflates lysosome positioning with autophagosome positioning — for ARL8A the safe shared target is lysosome localization, not autophagosome localization (PN term is narrower-but-mis-targeted: right process family, wrong cargo organelle).
Evidence alignment: PN cites tandfonline/NatComms titles (Arl8 review; BORC; RUFY3/4 = PMID:35314674). Review/notes anchor on PMID:16537643 (ARL8a/b lysosome localization), 25898167 (BORC), 28325809 (PLEKHM1), 35314674 (RUFY3/4). DR added PMID:27851960, 35653304 (cholesterol egress), 37213076 (exosomes, ARL8A/B dKO), 38296963 (DENND6A), 38128568 (BORCS8 disease) statement-only. Strong overlap (RUFY3/4); review broader.
Verdict: Consistent; PN GO:0061906 over-reaches for ARL8A (lysosome vs autophagosome positioning); review correctly declines and uses GO:0032418.
Recommended edits: none to ARL8A-ai-review.yaml. [MAP] do not propagate GO:0061906 to ARL8A from the autophagosome-localization leaf until direct ARL8A-dependent autophagosome positioning is shown; ARL8A's shared target is lysosome localization.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ARL8A/ARL8A-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Localization of the autophagosome | Movement of autophagosomes along microtubules | HOPS-BORC complex bridging

UniProt: Q96BM9
In branches: ALP
Notes: Small GTPase that regulates lysosome positioning and bridges the HOPS and BORC complexes for autophagosome-lysosome fusion. Also serves as a link to the dynein-dynactin system for vesicles.
PN references (titles):
- Arf-like GTPase Arl8: Moving from the periphery to the center of lysosomal biology (tandfonline.com)
- Full article: BORC coordinates encounter and fusion of lysosomes with autophagosomes (tandfonline.com)
- RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin | Nature Communications
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Localization of the autophagosome|Movement of autophagosomes along microtubules|HOPS-BORC complex bridging
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061906 autophagosome localization]
  rationale: This PN subtype denotes the bridging machinery that links HOPS/BORC-like late-endolysosomal transport systems to autophagosome positioning on microtubules. The best current GO target is autophagosome localization.
- [type] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Localization of the autophagosome|Movement of autophagosomes along microtubules
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061906 autophagosome localization]
  rationale: This leaf describes a mechanism for positioning autophagosomes. The safe shared GO target is autophagosome localization, not the downstream fusion process.
- [group] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Localization of the autophagosome
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061906 autophagosome localization]
  rationale: This group is explicitly about positioning/autophagosome localization in late autophagy. Autophagosome localization is the correct propagation target rather than autophagosome-lysosome fusion.
- [class] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a late macroautophagy context, but the subtree mixes docking, fusion, localization, membrane-composition, and unknown late-stage roles. The class-level relation is useful for display while propagation is restricted to narrower mechanism nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Autophagosome-lysosome docking | HOPS-BORC interaction mediator

UniProt: Q96BM9
In branches: ALP
Notes: Small GTPase that regulates lysosome positioning and bridges the HOPS and BORC complexes for autophagosome-lysosome fusion. Also serves as a link to the dynein-dynactin system for vesicles.
PN references (titles):
- Arf-like GTPase Arl8: Moving from the periphery to the center of lysosomal biology (tandfonline.com)
- Full article: BORC coordinates encounter and fusion of lysosomes with autophagosomes (tandfonline.com)
- RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin | Nature Communications
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Autophagosome-lysosome docking|HOPS-BORC interaction mediator
  status=context_only scope=too_broad_to_propagate GO=[GO:0061909 autophagosome-lysosome fusion]
  rationale: Reviewed as an interaction-mediator bucket in autophagosome-lysosome docking. The relation to fusion is contextual and should not project generic fusion to all members.
- [group] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Autophagosome-lysosome docking
  status=context_only scope=too_broad_to_propagate GO=[GO:0061909 autophagosome-lysosome fusion]
  rationale: Reviewed as an autophagosome-lysosome docking context. The subtree mixes component buckets and modulators, so generic fusion propagation should come only from narrower reviewed mechanism leaves.
- [class] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a late macroautophagy context, but the subtree mixes docking, fusion, localization, membrane-composition, and unknown late-stage roles. The class-level relation is useful for display while propagation is restricted to narrower mechanism nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

GO:0061906 autophagosome localization | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Localization of the autophagosome
GO:0061906 autophagosome localization | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Localization of the autophagosome|Movement of autophagosomes along microtubules
GO:0061906 autophagosome localization | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Localization of the autophagosome|Movement of autophagosomes along microtubules|HOPS-BORC complex bridging

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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

ARL8A

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human ARL8A (UniProt Q96BM9) — functional annotation

1) Target verification (gene/protein identity and disambiguation)

2) Key concepts and definitions (current understanding)

2.1 ARL8A is a lysosome-associated small GTPase

2.2 Functional definition: “Master organizer” of lysosome positioning and trafficking

3) Molecular mechanism and pathways (primary function, partners, localization)

3.1 Upstream recruitment to lysosomes: BORC → ARL8

3.2 Anterograde (plus-end) lysosome transport: ARL8-GTP → SKIP/PLEKHM2 → kinesin-1

3.3 Kinesin-3 coupling and track specialization: ARL8 → KIF1A/KIF1Bβ

3.4 Fusion/tethering and degradative trafficking: ARL8 → HOPS (and related effectors)

3.5 Bidirectional lysosome positioning (2024 update): ARL8 also contributes to retrograde programs

4) Recent developments and latest research (prioritizing 2023–2024)

4.1 Exosome secretion controlled by BORC–ARL8–HOPS-dependent endolysosome fusion (2023)

4.2 Human genetics links lysosome positioning machinery upstream of ARL8A to neurodevelopment (2024)

4.3 Cancer cohort associations (2024): ARL8A expression shows a non-significant survival trend

5) Current applications and real-world implementations

5.1 Research-use manipulation of lysosome positioning and function

5.2 Translational maturity

6) Expert opinions / authoritative synthesis

7) Statistics and quantitative data highlights (from included studies)

8) Functional summary (what ARL8A “does”)

Embedded summary artifact

Figure evidence (example quantitative association)

Limitations of the current evidence set

Artifacts

Citations

📚 Additional Documentation

Notes

ARL8A review notes

Deep research provider status

Evidence summary

PN projection decision

Falcon deep research findings (2026-06-07)

Pn Notes

ARL8A PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Localization of the autophagosome | Movement of autophagosomes along microtubules | HOPS-BORC complex bridging

PN row 2: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Autophagosome-lysosome docking | HOPS-BORC interaction mediator

Projected GO annotations (3)

Note

📄 View Raw YAML