Vps26 (CG14804) is the Drosophila ortholog of VPS26, an arrestin-fold subunit of the retromer cargo-selective complex (Vps35-Vps26-Vps29). Together with Vps35, Vps26 recognizes sorting motifs in the cytoplasmic tails of transmembrane cargo on endosomes and, with Snx3 or SNX-BAR sorting nexins, retrieves that cargo to the trans-Golgi network or recycles it to the plasma membrane, sparing it from lysosomal degradation. In flies, Vps26 is essential for development and is required for retromer-dependent retrieval of the Wnt cargo receptor Wntless, and hence for Wingless secretion, but not for Hedgehog or Dpp signalling. Retromer also retrieves Notch in neural progenitors, preventing ectopic Notch activation and tumorigenesis, maintains lysosomal degradative capacity in the fat body, and supports neuronal homeostasis together with the phospholipase iPLA2-VIA, which binds Vps26 and Vps35. In wing-disc epithelia Vps26 marks vesicles at an apical trafficking hub and is needed to maintain apical Crumbs and septate-junction delivery of the claudin-like protein Megatrachea.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:29909971 Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affect... | MODIFY | Summary: Binding to the phospholipase iPLA2-VIA (FBgn0036053). Reason: The IPI records Vps26 binding to iPLA2-VIA, the fly PLA2G6 homolog, which enhances retromer function. phospholipase binding is the informative term for this interaction. Proposed replacements: phospholipase binding Supporting Evidence: PMID:29909971 iPLA2-VIA binds the retromer subunits Vps35 and Vps26 and enhances retromer function to promote protein and lipid recycling. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: Generic location; less specific than the endosome localization. Reason: Correct but less specific than the evidence supports: Vps26 is a peripheral membrane protein of the retromer coat on endosomes, and endosome (GO:0005768) is already annotated to Vps26 (IBA, ISS). Proposed replacements: endosome Supporting Evidence: PMID:30176986 the retromer complex physically interacts with Notch and transports it away from early and late endosomes in a timely and efficient manner |
| GO:0005768 endosome | IBA GO_REF:0000033 | ACCEPT | Summary: Retromer acts on endosomes. Reason: The cargo-selective complex is recruited to endosomal membranes (by Rab7 and Snx3); fly retromer acts at early and late endosomes. IBA donors include mouse and plant VPS26. Supporting Evidence: PMID:30176986 the retromer complex physically interacts with Notch and transports it away from early and late endosomes in a timely and efficient manner |
| GO:0005768 endosome | ISS GO_REF:0000024 | ACCEPT | Summary: Retromer acts on endosomes. Reason: The cargo-selective complex is recruited to endosomal membranes (by Rab7 and Snx3); fly retromer acts at early and late endosomes. IBA donors include mouse and plant VPS26. Supporting Evidence: PMID:30176986 the retromer complex physically interacts with Notch and transports it away from early and late endosomes in a timely and efficient manner |
| GO:0005829 cytosol | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Cytosolic pool of a peripheral membrane complex. Reason: Retromer cycles between cytosol and endosome membranes; the functional location is the endosome. Inferred from the process annotation (GO_REF:0000108). Supporting Evidence: file:DROME/Vps26/Vps26-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006886 intracellular protein transport | IBA GO_REF:0000033 | MODIFY | Summary: Intracellular protein transport; correct but less specific than endosome-to-Golgi retrieval. Reason: Vps26 is required for retrieval of Wntless to the Golgi; the more specific process retrograde transport, endosome to Golgi (GO:0042147) is already annotated to Vps26 (IBA, ISS, NAS). IBA donors include fly Vps26 itself (FB:FBgn0014411). Proposed replacements: retrograde transport, endosome to Golgi Supporting Evidence: PMID:18193032 Wls localization and levels critically depend on retromer, a conserved protein complex that mediates endosome-to-Golgi protein trafficking in yeast |
| GO:0006886 intracellular protein transport | IEA GO_REF:0000002 | MODIFY | Summary: Intracellular protein transport; correct but less specific than endosome-to-Golgi retrieval. Reason: Vps26 is required for retrieval of Wntless to the Golgi; the more specific process retrograde transport, endosome to Golgi (GO:0042147) is already annotated to Vps26 (IBA, ISS, NAS). IBA donors include fly Vps26 itself (FB:FBgn0014411). Proposed replacements: retrograde transport, endosome to Golgi Supporting Evidence: PMID:18193032 Wls localization and levels critically depend on retromer, a conserved protein complex that mediates endosome-to-Golgi protein trafficking in yeast |
| GO:0006886 intracellular protein transport | IMP PMID:18193032 Wingless secretion promotes and requires retromer-dependent ... | MODIFY | Summary: Intracellular protein transport; correct but less specific than endosome-to-Golgi retrieval. Reason: Vps26 is required for retrieval of Wntless to the Golgi; the more specific process retrograde transport, endosome to Golgi (GO:0042147) is already annotated to Vps26 (IBA, ISS, NAS). IBA donors include fly Vps26 itself (FB:FBgn0014411). Proposed replacements: retrograde transport, endosome to Golgi Supporting Evidence: PMID:18193032 Wls localization and levels critically depend on retromer, a conserved protein complex that mediates endosome-to-Golgi protein trafficking in yeast |
| GO:0007224 smoothened signaling pathway | IMP NOT PMID:18193032 Wingless secretion promotes and requires retromer-dependent ... | ACCEPT | Summary: Retromer (Vps26) is not required for Hedgehog or Dpp signalling (NOT annotation). Reason: Port et al. found that Vps26/Vps35 loss blocks Wingless secretion through loss of Wntless, while Hh and Dpp signalling are unaffected, indicating no general role in exocytosis. The negative annotation is consistent with the UniProt summary of this study. Supporting Evidence: file:DROME/Vps26/Vps26-uniprot.txt The hh and dpp signaling pathways do not require the retromer complex |
| GO:0012505 endomembrane system | NAS PMID:26172538 Retromer Ensures the Degradation of Autophagic Cargo by Main... | MODIFY | Summary: Generic location; less specific than the endosome localization. Reason: Correct but less specific than the evidence supports: Vps26 is a peripheral membrane protein of the retromer coat on endosomes, and endosome (GO:0005768) is already annotated to Vps26 (IBA, ISS). Proposed replacements: endosome Supporting Evidence: PMID:30176986 the retromer complex physically interacts with Notch and transports it away from early and late endosomes in a timely and efficient manner |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: Generic location; less specific than the endosome localization. Reason: Correct but less specific than the evidence supports: Vps26 is a peripheral membrane protein of the retromer coat on endosomes, and endosome (GO:0005768) is already annotated to Vps26 (IBA, ISS). Proposed replacements: endosome Supporting Evidence: PMID:30176986 the retromer complex physically interacts with Notch and transports it away from early and late endosomes in a timely and efficient manner |
| GO:0030111 regulation of Wnt signaling pathway | IMP PMID:18193032 Wingless secretion promotes and requires retromer-dependent ... | MODIFY | Summary: Regulation of Wnt signalling; the evidence specifically supports a role in Wingless secretion. Reason: Loss of Vps26 impairs Wg secretion because Wntless is degraded rather than retrieved to the Golgi; the effect on Wnt signalling is via secretion of the ligand. The more specific term positive regulation of Wnt protein secretion (GO:0061357) captures the evidence (the same term is annotated to Vps35 from PMID:18193037). Proposed replacements: positive regulation of Wnt protein secretion Supporting Evidence: PMID:18193032 In the absence of the retromer components Dvps35 or Dvps26, but in presence of Wg, Wls is degraded and Wg secretion impaired. |
| GO:0030510 regulation of BMP signaling pathway | IMP NOT PMID:18193032 Wingless secretion promotes and requires retromer-dependent ... | ACCEPT | Summary: Retromer (Vps26) is not required for Hedgehog or Dpp signalling (NOT annotation). Reason: Port et al. found that Vps26/Vps35 loss blocks Wingless secretion through loss of Wntless, while Hh and Dpp signalling are unaffected, indicating no general role in exocytosis. The negative annotation is consistent with the UniProt summary of this study. Supporting Evidence: file:DROME/Vps26/Vps26-uniprot.txt The hh and dpp signaling pathways do not require the retromer complex |
| GO:0030904 retromer complex | IDA PMID:18193032 Wingless secretion promotes and requires retromer-dependent ... | MODIFY | Summary: Retromer complex; correct but less specific than the cargo-selective subcomplex. Reason: Vps26 is a subunit of the Vps35-Vps26-Vps29 cargo-selective trimer of retromer; retromer, cargo-selective complex (GO:0030906) is already annotated to Vps26 (IBA, ISS). Proposed replacements: retromer, cargo-selective complex Supporting Evidence: PMID:32286230 Retromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. |
| GO:0030904 retromer complex | NAS PMID:26172538 Retromer Ensures the Degradation of Autophagic Cargo by Main... | MODIFY | Summary: Retromer complex; correct but less specific than the cargo-selective subcomplex. Reason: Vps26 is a subunit of the Vps35-Vps26-Vps29 cargo-selective trimer of retromer; retromer, cargo-selective complex (GO:0030906) is already annotated to Vps26 (IBA, ISS). Proposed replacements: retromer, cargo-selective complex Supporting Evidence: PMID:32286230 Retromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. |
| GO:0030906 retromer, cargo-selective complex | IBA GO_REF:0000033 | ACCEPT | Summary: Vps26 is a core subunit of the retromer cargo-selective complex. Reason: Vps26 forms the cargo-selective trimer with Vps35 and Vps29; in fly Vps29 mutants Vps35 and Vps26 remain associated. IBA donors human VPS26A and yeast VPS26. Supporting Evidence: PMID:32286230 Vps35 and Vps26 proteins are normally expressed and associated |
| GO:0030906 retromer, cargo-selective complex | ISS GO_REF:0000024 | ACCEPT | Summary: Vps26 is a core subunit of the retromer cargo-selective complex. Reason: Vps26 forms the cargo-selective trimer with Vps35 and Vps29; in fly Vps29 mutants Vps35 and Vps26 remain associated. IBA donors human VPS26A and yeast VPS26. Supporting Evidence: PMID:32286230 Vps35 and Vps26 proteins are normally expressed and associated |
| GO:0032456 endocytic recycling | NAS PMID:26172538 Retromer Ensures the Degradation of Autophagic Cargo by Main... | ACCEPT | Summary: Retromer recycles cargo from endosomes back to the plasma membrane as well as to the TGN. Reason: In addition to TGN retrieval, the retromer cargo-selective complex recycles cargo such as Notch to the cell surface in fly neural progenitors. Supporting Evidence: PMID:30176986 Retromer (purple) normally interacts with Notch (green) and retrieves the pool of hypoubiquitinated Notch evading the ESCRT (cyan)-lysosomal degradation pathway and sends it back to the cell surface |
| GO:0038024 cargo receptor activity | IPI PMID:30176986 The retromer complex safeguards against neural progenitor-de... | MODIFY | Summary: Retromer binds Notch as cargo; retromer acts as a cytosolic cargo adaptor, not a transmembrane cargo receptor. Reason: Notch co-immunoprecipitates with retromer from larval brain and is retrieved by it, so Notch is a bona fide retromer cargo. GO cargo receptor activity is defined for membrane-spanning receptors that bind both cargo and coat adaptors; the cargo-recognition activity of the peripheral Vps35-Vps26-Vps29 trimer is cargo adaptor activity, contributed jointly by the subunits (contributes_to). Proposed replacements: cargo adaptor activity Supporting Evidence: PMID:30176986 Notch is a bona fide cargo protein of retromer |
| GO:0042147 retrograde transport, endosome to Golgi | IBA GO_REF:0000033 | ACCEPT | Summary: Core retromer process; Vps26 is needed to retrieve Wntless from endosomes to the Golgi. Reason: Wntless is degraded instead of being recycled to the Golgi in Vps26 mutants; conserved function of the cargo-selective complex (IBA donors mouse Vps26a/b, fission yeast). Supporting Evidence: PMID:18193032 Wls localization and levels critically depend on retromer, a conserved protein complex that mediates endosome-to-Golgi protein trafficking in yeast PMID:26172538 Retromer mediates the recycling of transmembrane proteins from endosomes to the trans-Golgi network |
| GO:0042147 retrograde transport, endosome to Golgi | ISS GO_REF:0000024 | ACCEPT | Summary: Core retromer process; Vps26 is needed to retrieve Wntless from endosomes to the Golgi. Reason: Wntless is degraded instead of being recycled to the Golgi in Vps26 mutants; conserved function of the cargo-selective complex (IBA donors mouse Vps26a/b, fission yeast). Supporting Evidence: PMID:18193032 Wls localization and levels critically depend on retromer, a conserved protein complex that mediates endosome-to-Golgi protein trafficking in yeast PMID:26172538 Retromer mediates the recycling of transmembrane proteins from endosomes to the trans-Golgi network |
| GO:0042147 retrograde transport, endosome to Golgi | NAS PMID:26172538 Retromer Ensures the Degradation of Autophagic Cargo by Main... | ACCEPT | Summary: Core retromer process; Vps26 is needed to retrieve Wntless from endosomes to the Golgi. Reason: Wntless is degraded instead of being recycled to the Golgi in Vps26 mutants; conserved function of the cargo-selective complex (IBA donors mouse Vps26a/b, fission yeast). Supporting Evidence: PMID:18193032 Wls localization and levels critically depend on retromer, a conserved protein complex that mediates endosome-to-Golgi protein trafficking in yeast PMID:26172538 Retromer mediates the recycling of transmembrane proteins from endosomes to the trans-Golgi network |
| GO:0099638 obsolete endosome to plasma membrane protein transport | IMP PMID:30176986 The retromer complex safeguards against neural progenitor-de... | MODIFY | Summary: Obsolete term; retromer returns Notch from endosomes to the cell surface. Reason: GO:0099638 is obsolete and was merged into endocytic recycling (GO:0032456). The cited study models retromer retrieving hypo-ubiquitinated Notch from endosomes back to the cell surface. Proposed replacements: endocytic recycling Supporting Evidence: PMID:30176986 Retromer (purple) normally interacts with Notch (green) and retrieves the pool of hypoubiquitinated Notch evading the ESCRT (cyan)-lysosomal degradation pathway and sends it back to the cell surface |
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Download this section (compressed HTML)Q: Do fly Vps26 and Vps35 bind Wntless and Notch through the conserved Vps26-Snx3 cargo-binding groove used for PhiX[LM] motifs in mammals?
Experiment: Structure-guided Vps26 point mutants that disrupt the Snx3/cargo-binding interface, tested for rescue of Wntless retrieval and Notch trafficking in vivo.
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