Affinage

VPS26B

Vacuolar protein sorting-associated protein 26B · UniProt Q4G0F5

Length
336 aa
Mass
39.2 kDa
Annotated
2026-06-11
21 papers in source corpus 12 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VPS26B is a paralog-specific subunit of the retromer complex that assembles into an alternative Vps26B-Vps29-Vps35 trimer and directs endosomal recycling of a distinct cargo repertoire (PMID:18088321, PMID:18656452). Structurally related to the arrestin family, VPS26B is incorporated into retromer through binding of Vps35 to a conserved C-terminal surface patch, an interaction required for its endosomal recruitment; VPS26B and VPS26A bind Vps35/Vps29 with nanomolar affinity and compete for a single site, defining mutually exclusive retromer complexes (PMID:18088321). VPS26B is essential for stability of the Vps26B-containing complex, as its loss severely reduces Vps35 while leaving the Vps26A complex intact (PMID:21040701). The two paralogous complexes diverge in cargo selection: VPS26B-retromer fails to sort CI-M6PR—a specificity governed by the VPS26B C-terminal variable region—instead routing the receptor to degradation, while supporting recycling of sortilin, GLUT1, the GPCR PAR-2, and neuronal glutamate receptors and SORL1 (PMID:21920005, PMID:21040701, PMID:26113136, PMID:34965419, PMID:32747499). Beyond canonical retromer recycling, VPS26B serves as a Rab14 effector within a RhoBTB3-SHIP164-VPS26B complex that drives lipid-transfer-dependent early endosome bud formation at Golgi-early endosome contacts (PMID:38565878), is phosphorylated by NEK1 to regulate endosomal trafficking (PMID:34376696), and is recruited together with TBC1D5 by murine cytomegalovirus M45 to support aggrephagy-mediated immune evasion (PMID:31844296).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 Medium

    Established whether VPS26B is a bona fide retromer component, answering whether the VPS26A paralog has a functional counterpart in the complex.

    Evidence Co-IP, yeast two-hybrid, fractionation and fluorescence imaging in HeLa/A549/HEK293 cells

    PMID:16190980

    Open questions at the time
    • Distinct localization from VPS26A described but cargo and functional role not defined
    • Direct binding interface with Vps35 not mapped
  2. 2007 High

    Defined the structural basis of VPS26B incorporation into retromer and showed the two paralogs form separate, competing complexes, framing the question of why two paralogous retromers exist.

    Evidence X-ray crystallography of mouse Vps26B with structure-based mutagenesis, quantitative in vitro binding and competition assays, in vivo co-IP

    PMID:18088321

    Open questions at the time
    • Functional consequence of distinct complexes not established
    • Cargo specificity differences not yet identified
  3. 2008 Medium

    Confirmed tissue-specific assembly of a discrete Vps26b retromer distinct from Vps26a/Vps26aT complexes, extending the paralog-specific model in vivo.

    Evidence Immunoprecipitation, pull-down, Western blot and RT-PCR in mouse testis

    PMID:18656452

    Open questions at the time
    • No cargo or trafficking function assigned in testis context
  4. 2010 Medium

    Showed VPS26B is required for stability of its own retromer complex and identified sortilin as a transport cargo, linking the paralog to specific endosome-to-TGN sorting.

    Evidence Vps26b knockout mice with Western blot and protein-level quantification

    PMID:21040701

    Open questions at the time
    • Mechanism of sortilin handover not resolved
    • Single lab; broader cargo set not surveyed
  5. 2011 High

    Resolved why the two paralogous retromers differ functionally by mapping cargo discrimination to the VPS26B C-terminal variable region, which excludes CI-M6PR.

    Evidence Reciprocal co-IP, deletion mutagenesis with rescue, and receptor/secretion trafficking assays in stable HEK293 lines

    PMID:21920005

    Open questions at the time
    • Structural basis of variable-region cargo exclusion not defined
    • Full cargo set distinguishing the paralogs incomplete
  6. 2015 Medium

    Demonstrated a physiological consequence of VPS26B recycling by showing it controls plasma membrane resensitization of the GPCR PAR-2.

    Evidence Calcium release, ERK1/2 signaling, and receptor resensitization assays in VPS26B-overexpressing HEK293 cells

    PMID:26113136

    Open questions at the time
    • Effect shown by overexpression; loss-of-function consequence not tested
    • Direct VPS26B-PAR-2 engagement not demonstrated
  7. 2019 Medium

    Identified a non-canonical role for VPS26B as part of the aggrephagy machinery, co-opted by a viral protein for immune evasion.

    Evidence Co-IP, protein aggregation and degradation assays, and M45 motif mutagenesis (MCMV system)

    PMID:31844296

    Open questions at the time
    • Endogenous (non-viral) aggrephagy role of VPS26B not established
    • How VPS26B/TBC1D5 link aggregates to LC3 mechanistically unclear
  8. 2020 Medium

    Used acute inactivation to define the cargo dependence of retromer, confirming GLUT1 requires retromer while CI-MPR sorting is comparatively retromer-independent.

    Evidence Knocksideways acute retromer inactivation with time-resolved quantitative trafficking assays in HeLa and H4 cells

    PMID:32747499

    Open questions at the time
    • VPS26A and VPS26B contributions not separated in this assay
    • Paralog-specific cargo not individually resolved
  9. 2021 Medium

    Placed VPS26B downstream of a kinase by showing NEK1 directly phosphorylates it to regulate endosomal trafficking, linking retromer to NEK1-RIPK1 pathway biology.

    Evidence In vitro kinase assay on VPS26B plus genetic epistasis (NEK1 KO rescued by RIPK1 inactivation) and trafficking assays in mice

    PMID:34376696

    Open questions at the time
    • Phosphosite(s) on VPS26B and their functional consequence not mapped
    • Direct link between phosphorylation and specific cargo not established
  10. 2021 Medium

    Established a dedicated neuronal function for VPS26B-organized retromer in recycling glutamate receptors and SORL1, connecting it to synaptic integrity.

    Evidence Mouse imaging, electrophysiology, immunocytochemistry, behavior, and VPS26B depletion

    PMID:34965419

    Open questions at the time
    • Direct cargo engagement vs. indirect effect not dissected
    • Molecular determinants of neuronal cargo selectivity unknown
  11. 2024 High

    Revealed a retromer-independent function in which VPS26B acts as a Rab14 effector driving early endosome bud formation through lipid transfer at Golgi-EE contacts.

    Evidence Co-IP complex identification, depletion with phenotypic rescue, live imaging, and lipid-transfer-defective mutant analysis

    PMID:38565878

    Open questions at the time
    • How VPS26B partitions between classic retromer and the RhoBTB3-SHIP164 complex unknown
    • Structural basis of VPS26B-SHIP164-RhoBTB3 assembly not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How VPS26B's phosphorylation, paralog-specific cargo selection, and distribution among its multiple complexes (retromer, RhoBTB3-SHIP164, aggrephagy) are coordinated in a single cell remains unresolved.
  • No unified regulatory model integrating NEK1 phosphorylation with complex choice
  • Structural definition of VPS26B in non-retromer complexes lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 1
Localization
GO:0005768 endosome 2 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-9609507 Protein localization 4 R-HSA-5653656 Vesicle-mediated transport 1 R-HSA-9612973 Autophagy 1
Partners
CP110GOLPH3NEK1RHOBTB3SHIP164TBC1D5VPS29VPS35
Complex memberships
RhoBTB3-SHIP164-VPS26B complexretromer (Vps26B-Vps29-Vps35)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Crystal structure of mouse Vps26B was determined, revealing a striking structural similarity to the arrestin family of proteins. Structure-based mutagenesis showed that both Vps26A and Vps26B are incorporated into retromer complexes through binding of Vps35 to a highly conserved surface patch within the C-terminal subdomain, and this interaction is required for endosomal recruitment of the proteins. X-ray crystallography, structure-based mutagenesis, biochemical binding assays Traffic (Copenhagen, Denmark) High 18088321
2007 Both Vps26A and Vps26B bind to Vps35/Vps29 with nanomolar affinity and compete for a single binding site, defining distinct retromer complexes in vitro and in vivo. In vitro binding assays (affinity measurements), competition assays, co-immunoprecipitation Traffic (Copenhagen, Denmark) High 18088321
2005 Vps26B is a peripheral membrane protein that co-precipitates with Vps35 from transfected cells; direct interaction was confirmed by yeast two-hybrid analysis, establishing Vps26B as a subunit of the retromer complex. In HeLa cells, Vps26B localizes to cytoplasm with low levels at the plasma membrane (distinct from Vps26A which is predominantly endosomal). In A549 cells, Vps26B co-localizes with actin-rich lamellipodia. TIRF microscopy confirmed plasma membrane association of CFP-Vps26B in HEK293 cells. Co-immunoprecipitation, yeast two-hybrid, subcellular fractionation, fluorescence microscopy, TIRF microscopy Traffic (Copenhagen, Denmark) Medium 16190980
2011 Vps26B-retromer associates with TBC1D5 and GOLPH3 (like Vps26A-retromer), but unlike Vps26A-retromer, Vps26B-retromer does not interact with CI-M6PR, leading to degradation of this receptor and increased cathepsin D secretion. Deletion of the variable Vps26B C-terminal region restores CI-M6PR cycling, indicating that this region directly controls differential cargo selection between the two paralogous retromer complexes. Co-immunoprecipitation, stable cell lines (HEK293 expressing Vps26A-myc or Vps26B-myc), deletion mutagenesis, receptor trafficking assays, secretion assays Traffic (Copenhagen, Denmark) High 21920005
2010 Vps26b knockout mice lack the Vps26b-Vps29-Vps35 retromer complex and show a severe reduction of Vps35 protein, while the Vps26a-Vps29-Vps35 complex remains intact. Sortilin protein levels are increased approximately 20% in Vps26b-deficient mice, implicating Vps26b-Vps29-Vps35 retromer in sortilin transport from endosomes to the TGN. Vps26b knockout mice, Western blot, co-immunoprecipitation, protein level quantification Biochemical and biophysical research communications Medium 21040701
2008 In mouse testis, Vps26b forms a Vps26b-Vps29-Vps35 retromer complex that is distinct from the Vps26a-Vps29-Vps35 and Vps26aT-Vps29-Vps35 complexes; direct interaction of Vps26b with Vps35 was demonstrated by immunoprecipitation and pull-down assay. Immunoprecipitation, pull-down assay, Western blot, RT-PCR Biochemical and biophysical research communications Medium 18656452
2019 Murine cytomegalovirus M45 protein recruits VPS26B and the LC3-interacting adaptor protein TBC1D5 to facilitate degradation of NEMO and RIPK1 protein aggregates by selective autophagy (aggrephagy), revealing VPS26B as a component of the aggrephagy machinery exploited for viral immune evasion. Co-immunoprecipitation, protein aggregation assays, autophagy/degradation assays, mutagenesis of M45 aggregation motif Nature microbiology Medium 31844296
2021 NEK1 kinase regulates retromer-mediated endosomal trafficking by directly phosphorylating VPS26B. NEK1 deficiency disrupts endosomal trafficking of plasma membrane proteins, and genetic inactivation of RIPK1 can rescue postnatal lethality and blood-brain barrier damage in NEK1-deficient mice. Kinase assay (phosphorylation of VPS26B by NEK1), genetic epistasis (NEK1 KO with RIPK1 inactivation rescue), endosomal trafficking assays Nature communications Medium 34376696
2015 Vps26B-retromer negatively regulates plasma membrane resensitization of PAR-2 (a protease-activated G protein-coupled receptor). Overexpression of Vps26B causes a significant delay in plasma membrane repopulation of PAR-2 following receptor stimulation, resulting in impaired PAR-2 activation after resensitization, without affecting initial receptor activation, ERK1/2 signaling, or endocytosis. Stable HEK293 cell line expressing Vps26B, calcium release assays, ERK1/2 signaling assays, receptor trafficking/resensitization assays Cell biology international Medium 26113136
2021 Neurons are enriched with a VPS26B-organized retromer core that is differentially dedicated to endosomal recycling. VPS26B regulates glutamate receptor and SORL1 recycling, and its depletion causes synaptic dysfunction particularly in the trans-entorhinal cortex. Mouse model imaging, electrophysiology, immunocytochemistry, behavioral assays, VPS26B depletion experiments Cell reports Medium 34965419
2020 Acute retromer inactivation (knocksideways technology applied to VPS26A/VPS26B-containing retromer) in HeLa and H4 cells causes time-resolved defects in cell surface sorting of GLUT1, but no quantifiable defect in CI-MPR sorting was detected, suggesting retromer has a comparatively limited role in ESCPE-1-mediated CI-MPR retrograde sorting. Knocksideways acute inactivation technology, quantitative trafficking assays Journal of cell science Medium 32747499
2022 Depletion of VPS26 (VPS26A or VPS26B) in mammalian cells leads to decreased primary ciliogenesis. Retromer co-immunoprecipitates with the centriolar protein CP110 and is required for CP110 removal from the mother centriole, defining a novel role for retromer in ciliogenesis. CRISPR/Cas9 knockout (C. elegans model), siRNA depletion in mammalian cells, co-immunoprecipitation, immunofluorescence ciliogenesis assay Journal of cell science Medium 35510502
2024 VPS26B forms a trimeric complex with SHIP164 and the ATPase RhoBTB3 at Golgi-early endosome contacts, acting as a novel Rab14 effector. This complex promotes early endosome bud formation through a lipid transfer-dependent mechanism; Rab14 activity regulates SHIP164 association with endosomes, and depletion of VPS26B phenocopies SHIP164 depletion (enlarged Rab14+ EEs without buds). Co-immunoprecipitation, protein complex identification, depletion/knockdown with phenotypic rescue, live imaging, lipid transfer-defective mutant analysis Cell discovery High 38565878

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Structure of Vps26B and mapping of its interaction with the retromer protein complex. Traffic (Copenhagen, Denmark) 99 18088321
2011 Vps26A and Vps26B subunits define distinct retromer complexes. Traffic (Copenhagen, Denmark) 87 21920005
2005 A novel mammalian retromer component, Vps26B. Traffic (Copenhagen, Denmark) 78 16190980
2019 Herpesviruses induce aggregation and selective autophagy of host signalling proteins NEMO and RIPK1 as an immune-evasion mechanism. Nature microbiology 56 31844296
2021 Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling. Cell reports 52 34965419
2010 Implication of mouse Vps26b-Vps29-Vps35 retromer complex in sortilin trafficking. Biochemical and biophysical research communications 51 21040701
2021 NEK1-mediated retromer trafficking promotes blood-brain barrier integrity by regulating glucose metabolism and RIPK1 activation. Nature communications 41 34376696
2016 Atypical parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins. The Journal of cell biology 38 27528657
2014 Genetic variability of the retromer cargo recognition complex in parkinsonism. Movement disorders : official journal of the Movement Disorder Society 23 25475142
2020 Dysregulation of the Retromer Complex System in Down Syndrome. Annals of neurology 22 32320094
2020 Acute inactivation of retromer and ESCPE-1 leads to time-resolved defects in endosomal cargo sorting. Journal of cell science 22 32747499
2023 Pharmacologic enhancement of retromer rescues endosomal pathology induced by defects in the Alzheimer's gene SORL1. Stem cell reports 19 37949073
2021 Viral Induced Protein Aggregation: A Mechanism of Immune Evasion. International journal of molecular sciences 19 34502533
2008 Identification of novel retromer complexes in the mouse testis. Biochemical and biophysical research communications 15 18656452
2023 Retromer Proteins Reduced in Down Syndrome and the Dp16 Model: Impact of APP Dose and Preclinical Studies of a γ-Secretase Modulator. Annals of neurology 9 37042072
2022 The retromer complex regulates C. elegans development and mammalian ciliogenesis. Journal of cell science 8 35510502
2015 Vps26B-retromer negatively regulates plasma membrane resensitization of PAR-2. Cell biology international 8 26113136
2025 Variations in rumen microbiota and host genome impacted feed efficiency in goat breeds. Frontiers in microbiology 7 39944650
2022 Identification of novel rare copy number variants associated with sporadic tetralogy of Fallot and clinical implications. Clinical genetics 7 35882632
2024 Biogenesis of Rab14-positive endosome buds at Golgi-endosome contacts by the RhoBTB3-SHIP164-Vps26B complex. Cell discovery 5 38565878
2011 Quantitative analysis of retromer complex-related genes during embryo development in the mouse. Molecules and cells 0 21359680

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