ARL3 (ADP-ribosylation factor-like 3) is a small Arf-family GTPase that acts as a cargo-release factor for lipidated ciliary proteins. In its GDP-bound form it is inactive. Inside the cilium it is loaded with GTP by its ciliary guanine nucleotide exchange factor ARL13B. ARL3-GTP binds the lipid-binding carrier proteins PDE6D (PDEdelta, for farnesylated/prenylated cargo such as INPP5E, GRK1, PDE6 subunits) and UNC119A/B (for myristoylated cargo such as NPHP3, transducin-alpha, cystin). This binding releases the cargo, so that lipidated proteins are deposited in the ciliary membrane. Because ARL13B is ciliary and the GTPase-activating protein RP2 is concentrated at the ciliary base and in the cytoplasm, ARL3 activity is polarized: cargo is released inside the cilium and the carriers are recycled after RP2 stimulates GTP hydrolysis. ARL3 also binds ARL2BP/BART and the BART-like protein CFAP36/BARTL1 through its N-terminal amphipathic helix. It is found in the cilium (prominently the photoreceptor connecting cilium), at centrosomes, on mitotic spindles and midbodies, at the Golgi, and in the cytoplasm and nucleus. ARL3 depletion impairs cytokinesis in HeLa cells. ARL3 variants cause Joubert syndrome and inherited retinal dystrophy, and mouse Arl3 loss causes photoreceptor degeneration and renal cysts.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Golgi membrane, from the UniProt subcellular location mapping. Reason: ARL3 has been seen at Golgi membranes, and RP2/ARL3 dysregulation affects Golgi cohesion and vesicle traffic toward the cilium. Its defined molecular role, however, is release of lipidated cargo in the cilium. Supporting Evidence: PMID:16525022 As seen in Figure 3D , even 10 min after addition of brefeldin A the Arl3 remained bound at the Golgi |
| GO:0000281 mitotic cytokinesis | IMP PMID:16525022 Arl2 and Arl3 regulate different microtubule-dependent proce... | KEEP AS NON CORE | Summary: ARL3 siRNA in HeLa cells causes failure of cytokinesis and binucleation. Reason: Experimental observation, retained. The mechanism is unresolved, and the role is separate from the established ciliary cargo-release function. Supporting Evidence: PMID:16525022 Knockdown of Arl3 by siRNA resulted in changes in cell morphology, increased acetylation of Ξ±-tubulin, failure of cytokinesis, and increased number of binucleated cells. |
| GO:0000287 magnesium ion binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Magnesium ion binding, by Ensembl Compara transfer from mouse. Reason: Arf-family GTPases coordinate Mg2+ with the bound nucleotide. Correct, but a cofactor feature, not a function. Notably, ARL3 nucleotide exchange depends less on Mg2+ than ARF exchange does. Supporting Evidence: PMID:8034651 In contrast to ARF proteins, the Arl3 protein has reduced dependence on phospholipids and magnesium for guanine nucleotide exchange. |
| GO:0001822 kidney development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Kidney development, by Ensembl Compara transfer from mouse (Arl3-null mice develop renal cysts). Reason: The renal phenotype is an organ-level consequence of defective ciliary protein targeting. It is kept as a non-core developmental process. |
| GO:0001822 kidney development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Kidney development, by similarity to mouse Arl3. Reason: As for the IEA kidney development row. |
| GO:0003924 GTPase activity | IEA GO_REF:0000120 | ACCEPT | Summary: GTPase activity, from combined automated methods. Reason: ARL3 hydrolyses GTP, but the intrinsic rate is very low and hydrolysis is driven by its GAP, RP2. The annotation is correct. G protein activity better captures the switch function. Supporting Evidence: PMID:18588884 Recently, we could identify RP2, responsible for a variant of X-linked retinitis pigmentosa, as the Arl3-specific GAP. |
| GO:0003925 G protein activity | IEA GO_REF:0000107 | ACCEPT | Summary: G protein activity, by Ensembl Compara transfer. Reason: ARL3 is a small-GTPase switch that cycles between GDP- and GTP-bound states. Its GEF is ARL13B and its GAP is RP2, and in the GTP-bound state it binds effectors (PDE6D, UNC119, ARL2BP, BARTL1). GO G protein activity explicitly covers small monomeric GTPases. Supporting Evidence: PMID:30269812 Both missense variants replace the highly conserved Arg149 residue, which we show to be necessary for the interaction with its guanine nucleotide exchange factor ARL13B file:human/ARL3/ARL3-deep-research-falcon.md with ARL13B/BART-dependent activation and RP2-dependent termination file:human/ARL3/ARL3-deep-research-falcon.md ARL3-GTP binds these carriers allosterically and promotes cargo release at the cilium; it is neither the lipid-modifying enzyme nor the cargoβs membrane transporter. |
| GO:0003925 G protein activity | ISS GO_REF:0000024 | ACCEPT | Summary: G protein activity, by similarity to mouse Arl3. Reason: Core molecular function, as for the IEA row. |
| GO:0005515 protein binding | IPI PMID:11847227 Functional overlap between retinitis pigmentosa 2 protein an... | MODIFY | Summary: Protein binding with RP2 (O75695), the ARL3-specific GTPase-activating protein; RP2 binds GTP-bound ARL3. Reason: Generic protein binding. The informative function from the GTPase side is binding to its GAP, RP2, which inactivates ARL3 after cargo release. Proposed replacements: GTPase activating protein binding Supporting Evidence: PMID:11847227 Finally, we find that RP2 interacts with GTP-bound ADP ribosylation factor-like 3 protein |
| GO:0005515 protein binding | IPI PMID:11847227 Functional overlap between retinitis pigmentosa 2 protein an... | MODIFY | Summary: Protein binding with ARL2BP (BART), from a targeted interaction study. Reason: Generic protein binding. ARL2BP (BART) is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:16169070 A human protein-protein interaction network: a resource for ... | MODIFY | Summary: Protein binding with PDE6D, from a high-throughput interaction screen. Reason: Generic protein binding. PDE6D is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:16169070 A human protein-protein interaction network: a resource for ... | MODIFY | Summary: Protein binding with UNC119, from a high-throughput interaction screen. Reason: Generic protein binding. UNC119 is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:18588884 Specificity of Arl2/Arl3 signaling is mediated by a ternary ... | MODIFY | Summary: Protein binding with PDE6D, from a targeted interaction study. Reason: Generic protein binding. PDE6D is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:18588884 Specificity of Arl2/Arl3 signaling is mediated by a ternary ... | MODIFY | Summary: Protein binding with UNC119, from a targeted interaction study. Reason: Generic protein binding. UNC119 is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | MODIFY | Summary: Protein binding with A6NIH7 (UNC119-family partner), from a targeted interaction study. Reason: Generic protein binding. A6NIH7 (UNC119-family partner) is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding Supporting Evidence: PMID:22085962 Furthermore, we found that binding of ARL3-GTP serves to release myristoylated cargo from UNC119. |
| GO:0005515 protein binding | IPI PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | MODIFY | Summary: Protein binding with UNC119, from a targeted interaction study. Reason: Generic protein binding. UNC119 is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding Supporting Evidence: PMID:22085962 Furthermore, we found that binding of ARL3-GTP serves to release myristoylated cargo from UNC119. |
| GO:0005515 protein binding | IPI PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | REMOVE | Summary: Protein binding with Q5TEA3, from a targeted interaction study. Reason: Generic protein binding with no functional context and no informative MF replacement. The interaction itself is not disputed. |
| GO:0005515 protein binding | IPI PMID:26455799 The Interaction of CCDC104/BARTL1 with Arl3 and Implications... | MODIFY | Summary: Protein binding with PDE6D, from a targeted interaction study. Reason: Generic protein binding. PDE6D is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding Supporting Evidence: PMID:26455799 The ciliary protein Arl3 has been shown to act as a specific release factor for myristoylated and farnesylated ciliary cargo molecules by binding to the effectors Unc119 and PDE6Ξ΄. |
| GO:0005515 protein binding | IPI PMID:26455799 The Interaction of CCDC104/BARTL1 with Arl3 and Implications... | MODIFY | Summary: Protein binding with UNC119, from a targeted interaction study. Reason: Generic protein binding. UNC119 is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding Supporting Evidence: PMID:26455799 The ciliary protein Arl3 has been shown to act as a specific release factor for myristoylated and farnesylated ciliary cargo molecules by binding to the effectors Unc119 and PDE6Ξ΄. |
| GO:0005515 protein binding | IPI PMID:26455799 The Interaction of CCDC104/BARTL1 with Arl3 and Implications... | MODIFY | Summary: Protein binding with ARL2BP (BART), from a targeted interaction study. Reason: Generic protein binding. ARL2BP (BART) is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding Supporting Evidence: PMID:26455799 The ciliary protein Arl3 has been shown to act as a specific release factor for myristoylated and farnesylated ciliary cargo molecules by binding to the effectors Unc119 and PDE6Ξ΄. |
| GO:0005515 protein binding | IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis... | MODIFY | Summary: Protein binding with UNC119, from a high-throughput interaction screen. Reason: Generic protein binding. UNC119 is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis... | MODIFY | Summary: Protein binding with ARL2BP (BART), from a high-throughput interaction screen. Reason: Generic protein binding. ARL2BP (BART) is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: Protein binding with UNC119, from a high-throughput interaction screen. Reason: Generic protein binding. UNC119 is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:30257685 Modifying Rap1-signalling by targeting Pde6Ξ΄ is neuroprotect... | MODIFY | Summary: Protein binding with PDE6D, from a targeted interaction study. Reason: Generic protein binding. PDE6D is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding Supporting Evidence: PMID:30257685 In absence of the compound, a host of previously described Pde6Ξ΄ binding partners were identified, including Arl3 and RPGR |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Protein binding with PDE6D, from a high-throughput interaction screen. Reason: Generic protein binding. PDE6D is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with O60907, from a high-throughput interaction screen. Reason: Generic protein binding with no functional context and no informative MF replacement. The interaction itself is not disputed. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Protein binding with UNC119, from a high-throughput interaction screen. Reason: Generic protein binding. UNC119 is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Protein binding with ARL2BP (BART), from a high-throughput interaction screen. Reason: Generic protein binding. ARL2BP (BART) is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Protein binding with PDE6D, from a high-throughput interaction screen. Reason: Generic protein binding. PDE6D is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Protein binding with ARL2BP (BART), from a high-throughput interaction screen. Reason: Generic protein binding. ARL2BP (BART) is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: Protein binding with PDE6D, from a high-throughput interaction screen. Reason: Generic protein binding. PDE6D is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: Protein binding with UNC119, from a high-throughput interaction screen. Reason: Generic protein binding. UNC119 is a GTP-dependent ARL3 effector: PDE6D and UNC119 proteins are lipid-binding carriers whose cargo is released when ARL3-GTP binds, and ARL2BP/BART binds active ARL2/ARL3. GTP-dependent protein binding is the informative replacement. Proposed replacements: GTP-dependent protein binding |
| GO:0005525 GTP binding | IBA GO_REF:0000033 | ACCEPT | Summary: GTP binding, by phylogenetic inference. Reason: ARL3 binds guanine nucleotides, as shown biochemically. Supporting Evidence: PMID:8034651 Purified recombinant human Arl3 was shown to bind guanine nucleotides but lacks ARF activity |
| GO:0005525 GTP binding | IDA PMID:18588884 Specificity of Arl2/Arl3 signaling is mediated by a ternary ... | ACCEPT | Summary: GTP binding, from biochemical characterization of Arl3βRP2βHRG4 (UNC119) complexes. Reason: Experimental support. |
| GO:0005525 GTP binding | IDA PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | ACCEPT | Summary: GTP-bound ARL3 releases myristoylated cargo from UNC119. Reason: Experimental support; GTP binding is required for effector engagement. Supporting Evidence: PMID:22085962 Furthermore, we found that binding of ARL3-GTP serves to release myristoylated cargo from UNC119. |
| GO:0005525 GTP binding | IEA GO_REF:0000120 | ACCEPT | Summary: GTP binding, from combined automated methods. Reason: Consistent with the experimental data. |
| GO:0005525 GTP binding | TAS PMID:8034651 ADP-ribosylation factor (ARF)-like 3, a new member of the AR... | ACCEPT | Summary: GTP binding, from the paper that identified Arl3. Reason: Supported by the nucleotide-binding data in this paper. Supporting Evidence: PMID:8034651 Purified recombinant human Arl3 was shown to bind guanine nucleotides but lacks ARF activity |
| GO:0005634 nucleus | IDA PMID:16525022 Arl2 and Arl3 regulate different microtubule-dependent proce... | KEEP AS NON CORE | Summary: ARL3 immunostaining in the nucleoplasm of cultured cells. Reason: Experimental, and agrees with the HPA nucleoplasm call. No nuclear function is known, and the authors themselves note that its significance is unclear. Supporting Evidence: PMID:16525022 the relationship of that observation to our localization of Arl3 to the nucleoplasm is not clear |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nucleus, from the UniProt subcellular location mapping. Reason: As for the IDA nucleus row. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Nucleoplasm, from Human Protein Atlas immunofluorescence. Reason: Agrees with published nucleoplasmic staining; no known nuclear function. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cytoplasm, by phylogenetic inference. Reason: ARL3 is a soluble GTPase with a large cytoplasmic pool, where RP2 inactivates it. Correct, but the cargo-release function takes place in the cilium. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasm, from the UniProt subcellular location mapping. Reason: As for the IBA cytoplasm row. |
| GO:0005794 Golgi apparatus | IDA PMID:16525022 Arl2 and Arl3 regulate different microtubule-dependent proce... | KEEP AS NON CORE | Summary: ARL3 staining at Golgi membranes, resistant to brefeldin A. Reason: Experimental observation of a non-core location. Supporting Evidence: PMID:16525022 As seen in Figure 3D , even 10 min after addition of brefeldin A the Arl3 remained bound at the Golgi |
| GO:0005813 centrosome | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Centrosome, from HPA immunofluorescence (Supported). Reason: Agrees with published centrosomal staining. The HPA basal-body call (Approved) is consistent with a pool at the ciliary base. |
| GO:0005813 centrosome | IDA PMID:16525022 Arl2 and Arl3 regulate different microtubule-dependent proce... | KEEP AS NON CORE | Summary: ARL3 at centrosomes in cultured cells. Reason: Experimental observation of a non-core location. Supporting Evidence: PMID:16525022 The presence of Arl3 in centrosomes, mitotic spindles, midzones, midbodies, and cilia are all supportive of roles in microtubule-dependent processes. |
| GO:0005813 centrosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Centrosome, from the UniProt subcellular location mapping. Reason: As for the experimental centrosome rows. |
| GO:0005819 spindle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Spindle, from the UniProt subcellular location mapping. Reason: ARL3 decorates mitotic spindles; non-core. |
| GO:0005876 spindle microtubule | IDA PMID:16525022 Arl2 and Arl3 regulate different microtubule-dependent proce... | KEEP AS NON CORE | Summary: ARL3 staining along spindle microtubules in mitotic HeLa cells. Reason: Experimental observation of a non-core location. Supporting Evidence: PMID:16525022 Arl3 staining was similar to that of acetylated Ξ±-tubulin in mitotic HeLa cells and was observed throughout the spindle, particularly in metaphase and anaphase |
| GO:0005881 cytoplasmic microtubule | IDA PMID:12417528 Localization in the human retina of the X-linked retinitis p... | KEEP AS NON CORE | Summary: ARL3 colocalizes with microtubules in HeLa cells, more strongly after taxol. Reason: Experimental, but non-core relative to the ciliary function. Supporting Evidence: PMID:12417528 Arl3 behaved as a microtubule-associated protein: it co-localized with microtubules in HeLa cells and this was enhanced following microtubule stabilization with taxol. |
| GO:0005929 cilium | IDA GO_REF:0000052 | ACCEPT | Summary: Cilium, from HPA immunofluorescence (primary cilium, Supported). Reason: Core location where ARL13B activates ARL3 and lipidated cargo is released. |
| GO:0005929 cilium | IDA PMID:16525022 Arl2 and Arl3 regulate different microtubule-dependent proce... | ACCEPT | Summary: ARL3 staining in cilia. Reason: Core location. Supporting Evidence: PMID:16525022 The presence of Arl3 in centrosomes, mitotic spindles, midzones, midbodies, and cilia are all supportive of roles in microtubule-dependent processes. |
| GO:0005929 cilium | IDA NOT PMID:17646400 Functional dissection of Rab GTPases involved in primary cil... | REMOVE | Summary: NOT located in cilium, from a GFP-tagged localization screen of Rab and Arl GTPases in serum-starved hTERT-RPE1 cells (Yoshimura et al. 2007), in which overexpressed EGFP-Arl family members other than ARL13B were not detected on primary cilia (Fig. S2 A). Reason: The full text shows the basis of the NOT is a negative result for an overexpressed EGFP-tagged construct in one cell line: Arl family GTPases "were also absent from primary cilia", and only Rab8a, Rabl5 and Arl13b showed cilium targeting. That establishes that GFP-ARL3 is not selectively targeted to or enriched in cilia under those conditions; it does not establish that ARL3 is absent or that its function lies outside the cilium. The function is defined inside the cilium: ARL13B, the ARL3 GEF, is confined to the ciliary membrane, so ARL3-GTP is generated inside the cilium, where it releases lipidated cargo from PDE6D and UNC119 (PMID:26551564). ARL3 is a soluble protein found throughout the cell and enriched in cilia; endogenous ARL3 stains cilia (PMID:16525022) and the photoreceptor connecting cilium (PMID:12417528). A NOT would be appropriate only if the function were shown to act outside the cilium, and the evidence shows the opposite. Supporting Evidence: PMID:17646400 In addition, Rabl4 and GTPases of the Arl family implicated in microtubule and cilia formation (Chiang et al., 2004; Schafer et al., 2006; Zhou et al., 2006; Qin et al., 2007) were also absent from primary cilia (Fig. S2 A). PMID:26551564 We had anticipated that in order for Arl3 to mediate cargo release inside cilia, an Arl3-specific GEF should be localized there as well. PMID:26551564 The highly conserved Arl3 β only present in ciliated organisms β localizes throughout the cell and is enriched in the primary cilium PMID:16525022 Correlative evidence in support of this hypothesis was found in that staining of Arl3 was strikingly similar to that of acetylated tubulin in interphase cells, spindles, cilia, and midbodies. PMID:12417528 In contrast, cofactor C and Arl3 localized predominantly to the photoreceptor connecting cilium in rod and cone photoreceptors. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5624130 | ACCEPT | Summary: Cilium, Reactome ciliary cargo trafficking reaction. Reason: Core location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5624133 | ACCEPT | Summary: Cilium, Reactome ciliary cargo trafficking reaction. Reason: Core location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638004 | ACCEPT | Summary: Cilium, Reactome ciliary cargo trafficking reaction. Reason: Core location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638006 | ACCEPT | Summary: Cilium, Reactome ciliary cargo trafficking reaction. Reason: Core location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638007 | ACCEPT | Summary: Cilium, Reactome ciliary cargo trafficking reaction. Reason: Core location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638016 | ACCEPT | Summary: Cilium, Reactome ciliary cargo trafficking reaction. Reason: Core location. |
| GO:0006892 post-Golgi vesicle-mediated transport | IMP PMID:20106869 The retinitis pigmentosa protein RP2 links pericentriolar ve... | KEEP AS NON CORE | Summary: RP2 depletion or constitutively active Arl3(Q71L) disperses Golgi-derived vesicles that carry cargo (such as IFT20) to the cilium. Reason: Experimental, kept. The effect concerns dysregulation of the ARL3 GTPase cycle on vesicle trafficking toward the ciliary base. It is plausibly downstream of, or parallel to, the core cargo-release function. Supporting Evidence: PMID:20106869 Depletion of RP2 and dysregulation of Arl3 resulted in dispersal of vesicles cycling cargo from the Golgi complex to the cilium, including the IFT protein IFT20. |
| GO:0006893 Golgi to plasma membrane transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Golgi to plasma membrane transport, by Ensembl Compara transfer from mouse (Arl3 needed for PKD1/PKD2 delivery from the TGN to cilia). Reason: Reflects ARL3's role in delivering membrane cargo to the cilium. Protein localization to cilium or ciliary membrane is the more accurate framing, and those terms are annotated. |
| GO:0006893 Golgi to plasma membrane transport | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Golgi to plasma membrane transport, by similarity to mouse. Reason: As for the IEA row. |
| GO:0007264 small GTPase-mediated signal transduction | IDA PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | MARK AS OVER ANNOTATED | Summary: Small GTPase-mediated signal transduction, from the ARL3βUNC119βRP2 cargo-targeting study. Reason: The paper describes a membrane-targeting GTPase cycle that delivers myristoylated proteins to the ciliary membrane. That is a protein-localization role, not transduction of a signal. The biology is better captured by protein localization to ciliary membrane and by G protein activity. Supporting Evidence: PMID:22085962 Our results uncover a selective, membrane targeting GTPase cycle that delivers myristoylated proteins to the ciliary membrane file:human/ARL3/ARL3-deep-research-falcon.md Ciliary signaling is chiefly a consequence of cargo composition, not a demonstrated direct receptor pathway for ARL3. |
| GO:0008017 microtubule binding | IDA PMID:12417528 Localization in the human retina of the X-linked retinitis p... | KEEP AS NON CORE | Summary: ARL3 co-purifies with microtubules from bovine brain. Reason: Experimental, kept. It may relate to the spindle, midbody and cytokinesis roles, but it is not the core ciliary cargo-release function. Supporting Evidence: PMID:12417528 Furthermore, Arl3 co-purified with microtubules from bovine brain. |
| GO:0015630 microtubule cytoskeleton | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Microtubule cytoskeleton, by phylogenetic inference. Reason: Consistent with microtubule association; non-core. |
| GO:0019003 GDP binding | IDA PMID:18588884 Specificity of Arl2/Arl3 signaling is mediated by a ternary ... | ACCEPT | Summary: GDP binding, from biochemical analysis of Arl2/Arl3 interactions. Reason: GDP-bound ARL3 is the inactive state of the switch. |
| GO:0019003 GDP binding | IEA GO_REF:0000120 | ACCEPT | Summary: GDP binding, from combined automated methods. Reason: Consistent with the experimental data. |
| GO:0030496 midbody | IDA PMID:16525022 Arl2 and Arl3 regulate different microtubule-dependent proce... | KEEP AS NON CORE | Summary: ARL3 stains the midbody. Reason: Experimental, linked to the cytokinesis phenotype; non-core. Supporting Evidence: PMID:16525022 Arl3 antisera stained the length of the midbody but staining was excluded from the midbody matrix |
| GO:0032391 photoreceptor connecting cilium | IDA PMID:12417528 Localization in the human retina of the X-linked retinitis p... | ACCEPT | Summary: ARL3 is concentrated in the photoreceptor connecting cilium of human retina. Reason: Experimental support for the photoreceptor ciliary pool, which is relevant to ARL3-dependent delivery of prenylated/myristoylated phototransduction proteins to outer segments. Supporting Evidence: PMID:12417528 In contrast, cofactor C and Arl3 localized predominantly to the photoreceptor connecting cilium in rod and cone photoreceptors. |
| GO:0042461 photoreceptor cell development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Photoreceptor cell development, by Ensembl Compara transfer from mouse. Reason: Photoreceptor defects in Arl3 mutants follow from failed delivery of lipidated outer-segment proteins. Kept as a non-core developmental process. Supporting Evidence: file:human/ARL3/ARL3-deep-research-falcon.md In mouse rods, removal of Arl3 after initial development selectively impaired trafficking of lipidated phototransduction proteins; earlier retina-wide deletion prevented formation of connecting cilia and outer segments. |
| GO:0042461 photoreceptor cell development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Photoreceptor cell development, by similarity to mouse. Reason: As for the IEA row. |
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cilium assembly, by phylogenetic inference. Reason: ARL3 orthologs affect cilium/flagellum formation in several lineages. In mouse, early retina-wide Arl3 deletion prevents connecting cilium and outer segment formation, so a requirement for ciliogenesis exists at least in photoreceptors. However, Joubert patient ARL3 fibroblasts retain morphologically normal cilia, and the defined molecular role is release of lipidated cargo (membrane composition) rather than axoneme building. Kept as non-core. Supporting Evidence: file:human/ARL3/ARL3-deep-research-falcon.md Thus both insufficient and excessive activity disrupt retinal cell biology, although the earliest embryonic deletion also demonstrates a broader requirement for normal ciliogenesis. |
| GO:0060271 cilium assembly | IMP PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | KEEP AS NON CORE | Summary: Zebrafish arl3 morphants show ciliopathy-like phenotypes (body curvature, Kupffer's vesicle defects). Reason: Experimental and kept. The zebrafish morphant phenotypes fit defective ciliary function. Mouse photoreceptor data also show a requirement for ciliogenesis when Arl3 is deleted early, but the core ARL3 role is cargo release, so this is non-core. Supporting Evidence: PMID:22085962 MO-mediated knockdown of genes involved in ciliary function typically result in curved body, defects in the size of the ciliated embryonic structure known as the Kupffer's vesicle (KV), and reduced visual function |
| GO:0061512 protein localization to cilium | IMP PMID:30269812 ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary ... | ACCEPT | Summary: Joubert syndrome ARL3 Arg149 variants abolish ARL13B binding and reduce ciliary INPP5E and NPHP3. Reason: Core process. ARL3-GTP releases lipidated cargo from its carriers inside the cilium, so ARL3 does part of the work of protein localization to the cilium. Supporting Evidence: PMID:30269812 ARL3-mutant cilia demonstrated a significant loss of both INPP5E and NPHP3 content (Figure 4 and Figures S4βS6), indicating that WT ARL3 is required for normal release of these cargos into the ciliary axoneme. |
| GO:0061512 protein localization to cilium | ISS GO_REF:0000024 | ACCEPT | Summary: Protein localization to cilium, by similarity to mouse Arl3. Reason: Core process. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Extracellular exosome, from urinary exosome proteomics. Reason: High-throughput detection of no known functional significance. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. |
| GO:1903441 protein localization to ciliary membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Protein localization to ciliary membrane, by Ensembl Compara transfer. Reason: Core process. ARL3-GTP releases myristoylated NPHP3 from UNC119B so that it is targeted to the ciliary membrane. Supporting Evidence: PMID:22085962 Finally, we showed that ARL3, UNC119b (but not UNC119a), and the ARL3 GAP Retinitis Pigmentosa 2 (RP2) are required for NPHP3 ciliary targeting |
| GO:1903441 protein localization to ciliary membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Protein localization to ciliary membrane, by similarity. Reason: Core process. Supporting Evidence: PMID:22085962 Our results uncover a selective, membrane targeting GTPase cycle that delivers myristoylated proteins to the ciliary membrane |
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Download this section (compressed HTML)Q: Is the cytokinesis/midbody role of ARL3 (from HeLa siRNA) mechanistically linked to its cargo-release function, for example via PDE6D/UNC119 cargo at the midbody, or is it independent?
Q: What is the basis of the negative ciliary localization reported in the Rab/Arl localization screen (PMID:17646400), given the positive endogenous and HPA ciliary data?
Experiment: Test whether ARL3 knockout cells rescued with ARL13B-binding-deficient ARL3 (R149H/C) still complete cytokinesis normally, while failing to target INPP5E and NPHP3 to cilia.
Hypothesis: ARL3's role in cytokinesis is independent of ARL13B-driven cargo release.
Type: knockout rescue with separation-of-function mutants
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