UNC119B is a soluble myristoyl-binding cargo carrier of the PDE6D/UNC119 family. Its immunoglobulin-like beta-sandwich forms a hydrophobic pocket, lined by conserved phenylalanines, that sequesters the N-terminal myristoyl group of a subset of myristoylated proteins such as nephrocystin-3 (NPHP3) and cystin. UNC119B shuttles these lipidated cargoes through the cytosol to the primary cilium, where it concentrates at the transition zone and proximal axoneme. Inside the cilium, GTP-bound ARL3 (activated by ARL13B) binds UNC119B and allosterically releases the myristoylated cargo into the ciliary membrane; the ARL3 GTPase-activating protein RP2 then returns ARL3 to the GDP state, freeing the carrier for another round. Through this ARL13B-ARL3-RP2 cycle UNC119B targets myristoylated proteins to the ciliary membrane, distinct from the PDE6D route used by prenylated cargo.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | MODIFY | Summary: UNC119B binds ARL3 (P36405); ARL3-GTP binding releases myristoylated cargo from UNC119B. Reason: UNC119B is an ARL3 effector; binding of ARL3-GTP allosterically opens the myristoyl pocket to release cargo. Small GTPase binding captures this regulated effector interaction better than generic protein binding. Proposed replacements: small GTPase binding Supporting Evidence: PMID:22085962 Furthermore, we found that binding of ARL3-GTP serves to release myristoylated cargo from UNC119. PMID:22960633 Similar effects were seen for the interaction of UNC119b complexes, which also showed specificity for Arl3 |
| GO:0005515 protein binding | IPI PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | REMOVE | Summary: UNC119B binds myristoylated cystin (CYS1, Q717R9) through its myristoyl-binding pocket. Reason: Generic protein binding is uninformative. The interaction itself is real and is the myristoyl-dependent capture of lipidated cargo, which is already represented by the lipid binding (GO:0008289) IDA/IBA annotations; removal does not mean the interaction is false. Supporting Evidence: PMID:22085962 Here we report that UNC119 is a myristoyl-binding protein that binds to a subset of myristoylated proteins, including NPHP3 and cystin, and that the small GTPase ARL3 regulates myristoyl–cargo binding. |
| GO:0005515 protein binding | IPI PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | REMOVE | Summary: UNC119B binds myristoylated NPHP3 (Q7Z494) in a myristoylation-dependent manner. Reason: Generic protein binding is uninformative. The interaction itself is real and is the myristoyl-dependent capture of lipidated cargo, which is already represented by the lipid binding (GO:0008289) IDA/IBA annotations; removal does not mean the interaction is false. Supporting Evidence: PMID:22085962 Here we report that UNC119 is a myristoyl-binding protein that binds to a subset of myristoylated proteins, including NPHP3 and cystin, and that the small GTPase ARL3 regulates myristoyl–cargo binding. |
| GO:0005515 protein binding | IPI PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | REMOVE | Summary: UNC119B co-purifies with MACIR (C5orf30, Q96GV9); MACIR binding occurs only when UNC119B is unliganded. Reason: Generic protein binding is uninformative and the functional meaning of the MACIR interaction is unknown; no more specific activity can be assigned from interaction data alone. Removal does not mean the interaction is false. Supporting Evidence: file:human/UNC119B/UNC119B-uniprot.txt Interacts with MACIR; interaction only takes |
| GO:0005515 protein binding | IPI PMID:22960633 Structural basis for Arl3-specific release of myristoylated ... | REMOVE | Summary: Nanomolar binding of UNC119B to an NPHP3 myristoylated peptide was measured. Reason: Generic protein binding is uninformative. The interaction itself is real and is the myristoyl-dependent capture of lipidated cargo, which is already represented by the lipid binding (GO:0008289) IDA/IBA annotations; removal does not mean the interaction is false. Supporting Evidence: PMID:22960633 Binding to UNC119b was very similar with Kds of 8 and 27 nM, respectively |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interactome detection of UNC119B-NPHP3. Reason: Generic protein binding is uninformative. The interaction itself is real and is the myristoyl-dependent capture of lipidated cargo, which is already represented by the lipid binding (GO:0008289) IDA/IBA annotations; removal does not mean the interaction is false. This row derives from a proteome-scale screen and adds no functional information. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5624131 | ACCEPT | Summary: Reactome places the UNC119B-cargo binding step in the cytosol. Reason: UNC119B is a soluble carrier that extracts and shuttles myristoylated proteins through the cytoplasm before ciliary release; a cytosolic pool is expected for this mechanism. Supporting Evidence: PMID:22960633 UNC119/HRG4 is responsible for ciliary delivery of myristoylated cargo. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5624132 | ACCEPT | Summary: Reactome places UNC119B-stimulated cargo translocation starting in the cytosol. Reason: Consistent with a soluble lipid-cargo carrier; see the other cytosol row. Supporting Evidence: PMID:22960633 UNC119/HRG4 is responsible for ciliary delivery of myristoylated cargo. |
| GO:0005929 cilium | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: cilium localization inherited in the UNC119 clade. Reason: Direct localization of tagged UNC119B to the transition zone and proximal cilium in RPE cells supports this phylogenetically inferred location. Supporting Evidence: PMID:22085962 More importantly, the LAP-UNC119b was enriched at the transition zone and extended into the proximal end of the cilium |
| GO:0005929 cilium | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to cilium. Reason: Supported by direct localization data. Supporting Evidence: PMID:22085962 More importantly, the LAP-UNC119b was enriched at the transition zone and extended into the proximal end of the cilium |
| GO:0005929 cilium | TAS Reactome:R-HSA-5624130 | ACCEPT | Summary: Reactome: myristoylated NPHP3 translocates into the ciliary membrane. Reason: The Reactome cilium steps describe the ARL3-UNC119B-RP2 cycle that takes place in the cilium. Supporting Evidence: PMID:22085962 More importantly, the LAP-UNC119b was enriched at the transition zone and extended into the proximal end of the cilium PMID:22085962 Furthermore, we found that binding of ARL3-GTP serves to release myristoylated cargo from UNC119. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5624132 | ACCEPT | Summary: Reactome: UNC119B stimulates translocation of myristoylated ciliary cargo to the cilium. Reason: Consistent with experimental localization. Supporting Evidence: PMID:22085962 More importantly, the LAP-UNC119b was enriched at the transition zone and extended into the proximal end of the cilium |
| GO:0005929 cilium | TAS Reactome:R-HSA-5624133 | ACCEPT | Summary: Reactome: ARL3-GTP binds the UNC119B complex in the cilium. Reason: Consistent with experimental localization. Supporting Evidence: PMID:22085962 Furthermore, we found that binding of ARL3-GTP serves to release myristoylated cargo from UNC119. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638004 | ACCEPT | Summary: Reactome: RP2 binds ARL3-GTP-UNC119B. Reason: Consistent with experimental localization. Supporting Evidence: PMID:22085962 More importantly, the LAP-UNC119b was enriched at the transition zone and extended into the proximal end of the cilium |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638006 | ACCEPT | Summary: Reactome: ARL3 hydrolyzes GTP (UNC119B complex in cilium). Reason: Consistent with experimental localization. Supporting Evidence: PMID:22085962 More importantly, the LAP-UNC119b was enriched at the transition zone and extended into the proximal end of the cilium |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638007 | ACCEPT | Summary: Reactome: RP2 activates ARL3 GTPase activity (UNC119B complex in cilium). Reason: Consistent with experimental localization. Supporting Evidence: PMID:22085962 More importantly, the LAP-UNC119b was enriched at the transition zone and extended into the proximal end of the cilium |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638016 | ACCEPT | Summary: Reactome: RP2-ARL3-GDP-UNC119B dissociates. Reason: Consistent with experimental localization. Supporting Evidence: PMID:22085962 More importantly, the LAP-UNC119b was enriched at the transition zone and extended into the proximal end of the cilium |
| GO:0008289 lipid binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: lipid (myristoyl) binding inherited across the PDE6D/UNC119 family. Reason: The hydrophobic beta-sandwich pocket that binds acyl/prenyl groups is a family-wide property, and UNC119B myristoyl binding is experimentally established. GO no longer has a specific myristoyl-binding term (N-terminal myristoylation domain binding, GO:0031997, is obsolete), so lipid binding is the appropriate level. Supporting Evidence: PMID:22085962 Here we report that UNC119 is a myristoyl-binding protein that binds to a subset of myristoylated proteins, including NPHP3 and cystin, and that the small GTPase ARL3 regulates myristoyl–cargo binding. |
| GO:0008289 lipid binding | IDA PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | ACCEPT | Summary: UNC119B binds the myristoyl moiety of cargo; phenylalanine mutants in the pocket abolish binding. Reason: Direct biochemical evidence (myristoylated peptide pull-downs and pocket mutants) shows UNC119B binds the myristoyl lipid of its cargo. This is the core molecular activity. Supporting Evidence: PMID:22085962 Here we report that UNC119 is a myristoyl-binding protein that binds to a subset of myristoylated proteins, including NPHP3 and cystin, and that the small GTPase ARL3 regulates myristoyl–cargo binding. PMID:22085962 Strikingly, the myristoyl-binding mutant tdTomato-UNC119b Mut-4 failed to rescue to the same extent, indicating that NPHP3 ciliary targeting indeed requires the myristoyl-binding activity of UNC119b. file:human/UNC119B/UNC119B-deep-research-falcon.md UNC119 proteins preferentially carry N-myristoylated cargo, whereas PDE6D is primarily a prenyl-cargo carrier. |
| GO:0035869 ciliary transition zone | IDA PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | ACCEPT | Summary: Tagged UNC119B is enriched at the ciliary transition zone and proximal cilium. Reason: Direct localization in human RPE cells. Supporting Evidence: PMID:22085962 More importantly, the LAP-UNC119b was enriched at the transition zone and extended into the proximal end of the cilium |
| GO:0042953 lipoprotein transport | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: lipoprotein (lipidated protein) transport by UNC119 family carriers. Reason: UNC119 proteins carry lipid-modified proteins to target membranes; the GO definition of lipoprotein transport (movement of a protein conjugated to lipid) fits the delivery of myristoylated cargo. 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 and that targeting requires UNC119b myristoyl-binding activity. |
| GO:0042953 lipoprotein transport | IDA PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | ACCEPT | Summary: UNC119B and its myristoyl-binding activity are required for ciliary targeting of myristoylated NPHP3. Reason: siRNA/rescue experiments show UNC119B myristoyl binding is needed to deliver myristoylated NPHP3 to the cilium; UNC119B itself carries the cargo, so it performs the transport step. A more specific complementary process is protein localization to ciliary membrane (GO:1903441), captured in core_functions. 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 and that targeting requires UNC119b myristoyl-binding activity. PMID:22085962 Strikingly, the myristoyl-binding mutant tdTomato-UNC119b Mut-4 failed to rescue to the same extent, indicating that NPHP3 ciliary targeting indeed requires the myristoyl-binding activity of UNC119b. |
| GO:0042953 lipoprotein transport | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning annotation to lipoprotein transport. Reason: Agrees with the experimental evidence. 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 and that targeting requires UNC119b myristoyl-binding activity. |
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: cilium assembly inferred for the UNC119 clade. Reason: Morphant data in zebrafish and nematode unc-119 phenotypes point to ciliary roles, but in human cells UNC119B depletion selectively blocks myristoylated cargo entry without disrupting other ciliary delivery; cilia still form. Any role in cilium assembly is likely indirect, via cargo delivery, so this is kept as non-core. Supporting Evidence: PMID:22085962 S5), indicating that delivery of nonmyristoylated proteins to the cilium is not disrupted by the depletion of ARL3 pathway components. PMID:22085962 Furthermore, in zebrafish, knockdown of unc119a lead to three cilia-related phenotypes (curved body, KV defect, and vision impairment), while unc119b depletion displayed only a mild KV defect, supporting differential roles for unc119a and unc119b in vivo. |
| GO:0060271 cilium assembly | IMP PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | KEEP AS NON CORE | Summary: Morpholino knockdown phenotypes in zebrafish (Kupffer vesicle, body curvature) attributed to UNC119B. Reason: The curator read the full text and the zebrafish data indicate ciliary dysfunction; however the phenotype (Kupffer vesicle size, curved body) does not show that UNC119B builds the axoneme, and human cells lacking UNC119B still form cilia. Retained as a non-core, likely indirect role. Supporting Evidence: PMID:22085962 Furthermore, in zebrafish, knockdown of unc119a lead to three cilia-related phenotypes (curved body, KV defect, and vision impairment), while unc119b depletion displayed only a mild KV defect, supporting differential roles for unc119a and unc119b in vivo. |
| GO:0097225 sperm midpiece | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence call in sperm midpiece. Reason: HPA antibody-based tissue localization; the sperm flagellum is a motile cilium, so localization there is plausible for a ciliary lipid-cargo carrier, but no functional data exist for UNC119B in sperm. The original image was not inspected. |
| GO:0097228 sperm principal piece | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence call in sperm principal piece. Reason: As for sperm midpiece: plausible flagellar localization without functional characterization; image not inspected. |
| GO:0097229 sperm end piece | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence call in sperm end piece. Reason: As for sperm midpiece: plausible flagellar localization without functional characterization; image not inspected. |
| GO:1903441 protein localization to ciliary membrane | IMP PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | NEW | Summary: Proposed NEW annotation. UNC119B, through its myristoyl-binding pocket, carries myristoylated NPHP3 to the ciliary membrane; knockdown abolishes and pocket mutants fail to rescue NPHP3 ciliary targeting. Reason: Participation test: UNC119B is itself the carrier that binds and delivers the lipidated cargo, so it performs a step of the localization process rather than merely being required for it. Comparator: the paralogous lipid-cargo carrier PDE6D carries protein localization to cilium (GO:0061512) in GOA. The existing lipoprotein transport term does not capture the ciliary-membrane destination. Non-myristoylated cargo (GPCRs) is unaffected, consistent with a cargo-specific carrier role. 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 and that targeting requires UNC119b myristoyl-binding activity. PMID:22085962 Strikingly, the myristoyl-binding mutant tdTomato-UNC119b Mut-4 failed to rescue to the same extent, indicating that NPHP3 ciliary targeting indeed requires the myristoyl-binding activity of UNC119b. PMID:22085962 S5), indicating that delivery of nonmyristoylated proteins to the cilium is not disrupted by the depletion of ARL3 pathway components. |
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Download this section (compressed HTML)Q: Is the reported lipidation-independent allosteric activation of the kinase PSKH1 by UNC119B physiologically relevant, and where in the cell does it occur?
Q: What determines which myristoylated proteins are selected by UNC119B rather than UNC119A, given that both bind NPHP3 peptides with similar affinity in vitro?
Q: Does UNC119B deliver myristoylated cargo (e.g., NPHP3, cystin) in photoreceptors and sperm flagella, where HPA and UniProt suggest expression?
Q: Is the zebrafish and nematode ciliary phenotype a consequence of failed myristoylated cargo delivery, or does UNC119B have a cargo-independent role in cilium assembly?
Experiment: Generate UNC119B knockout human RPE1 cells, quantify cilium frequency/length and ciliary NPHP3/cystin, and rescue with wild-type versus myristoyl-pocket (phenylalanine) mutant UNC119B.
Hypothesis: Ciliary defects after UNC119B loss are explained entirely by loss of myristoylated cargo delivery.
Type: Genetic knockout and separation-of-function rescue
Experiment: Proximity labeling or myristoyl-click chemistry pull-down from cells lacking UNC119A or UNC119B to define paralog-specific cargoes.
Hypothesis: UNC119B has a defined myristoylated cargo repertoire distinct from UNC119A.
Type: Chemical proteomics
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