Affinage

TBC1D5

TBC1 domain family member 5 · UniProt Q92609

Length
795 aa
Mass
89.0 kDa
Annotated
2026-06-10
19 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBC1D5 is a Rab-GAP that inactivates Rab7 to control the membrane association cycle of the retromer cargo-selective complex, positioning it as a central regulator linking endosomal maturation, retrograde cargo recycling, and autophagy (PMID:19531583, PMID:29158324). It docks onto the retromer VPS29 subunit through a loop that inserts into a conserved hydrophobic pocket opposite the VPS29–VPS35 interface, and loss of this interaction produces defective retromer-dependent receptor trafficking (PMID:27827364). By driving Rab7-GTP hydrolysis, TBC1D5 confines active Rab7 in space: its loss causes Rab7 hyperactivation that spreads across the lysosomal domain, depletes the inactive endomembrane Rab7 pool, misroutes ATG9a, and impairs autophagosome formation during Parkin-mediated mitophagy (PMID:29158324). Beyond Rab7a, TBC1D5 acts as a GAP for Rab7b, an activity stimulated by retromer, and controls CI-MPR- and sortilin-positive vesicle numbers (PMID:30111580). TBC1D5 toggles between inhibiting retromer and being sequestered onto LC3+ compartments: during metabolic stress it is captured via its LIR motif, relieving retromer inhibition to enable GLUT1 surface recycling, while in autophagy-deficient cells persistent inhibition causes GLUT1 missorting (PMID:28602638). It additionally associates with ATG9, the ULK1 complex, clathrin and AP2 to direct ATG9 sorting during autophagy (PMID:24603492), and phagophores can capture retromer–TBC1D5 endosomes for bulk lysosomal turnover (PMID:37938196). This hub is targeted by multiple pathogens — the Legionella effector RidL competitively displaces TBC1D5 from VPS29 to promote bacterial replication (PMID:29146912), and SARS-CoV-2 ORF3a sequesters TBC1D5 to hyperactivate Rab7 and impair CI-M6PR retrieval (PMID:38448435). In Drosophila, TBC1D5 constrains synaptic growth by limiting BMP receptor levels through Rab7 and retromer (PMID:36473687).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2009 High

    Established TBC1D5 as a retromer-associated Rab-GAP, answering whether a TBC-domain protein gates retromer membrane recruitment.

    Evidence Co-IP, membrane fractionation, and dominant-negative Rab7 analysis in cells

    PMID:19531583

    Open questions at the time
    • Did not define the structural basis of the TBC1D5–retromer interaction
    • Direct GAP activity toward Rab7 not biochemically reconstituted here
  2. 2014 High

    Linked TBC1D5 to autophagy by showing it associates with ATG9 and the autophagy machinery and is required for correct ATG9 sorting.

    Evidence Co-IP, siRNA depletion, and autophagy-induction imaging with ATG9 cargo readout

    PMID:24603492

    Open questions at the time
    • Mechanism coupling TBC1D5 GAP activity to ATG9 sorting not resolved
    • Role of clathrin/AP2 in recruiting TBC1D5 incompletely defined
  3. 2016 High

    Defined the atomic basis of TBC1D5 docking onto retromer, showing a GAP-domain loop inserts into a VPS29 hydrophobic pocket.

    Evidence X-ray crystallography with binding assays, mutagenesis, and cell-based trafficking assays

    PMID:27827364

    Open questions at the time
    • Did not capture the Rab7-bound catalytic state
    • Regulation of the docked complex on membranes not addressed
  4. 2017 High

    Showed TBC1D5/retromer spatially restrict Rab7 activity, and that its loss causes Rab7 hyperactivation that disrupts ATG9 routing and mitophagy.

    Evidence siRNA depletion, live imaging, FRAP, and Parkin-mitophagy assays

    PMID:29158324

    Open questions at the time
    • How retromer stimulates TBC1D5 GAP activity in cells not detailed
    • Compartment-specific recruitment cues unresolved
  5. 2017 High

    Revealed an autophagy-gated switch in which LIR-dependent sequestration of TBC1D5 relieves retromer inhibition to drive GLUT1 surface recycling.

    Evidence Autophagy induction/inhibition, depletion and rescue, surface biotinylation, and Co-IP

    PMID:28602638

    Open questions at the time
    • Signals controlling LIR-mediated capture beyond metabolic stress not mapped
    • Quantitative partitioning between retromer and LC3 pools unknown
  6. 2018 High

    Extended TBC1D5 substrate range to Rab7b and showed retromer stimulates this GAP activity, broadening its trafficking control.

    Evidence siRNA screen, Co-IP, in vitro GAP assay, and cell-based trafficking readouts

    PMID:30111580

    Open questions at the time
    • Relative physiological contribution of Rab7a vs Rab7b not quantified
    • Structural basis of Rab7b recognition not determined
  7. 2018 Medium

    Demonstrated that pharmacological TBC1D5 inhibition is a gain-of-function lever for retromer sorting, linking GAP suppression to enhanced endosomal recycling.

    Evidence Chemical inhibition with Rab7a activation (RILP pulldown) and retromer imaging

    PMID:29777037

    Open questions at the time
    • Limited mechanistic depth on inhibitor selectivity
    • Long-term consequences of sustained inhibition not assessed
  8. 2020 High

    Showed pathogens hijack the TBC1D5–VPS29 interface: Legionella RidL competitively displaces TBC1D5 to promote bacterial replication.

    Evidence Crystal structure of RidL–Vps29, mutagenesis, Co-IP, and intracellular replication assays

    PMID:29146912

    Open questions at the time
    • Downstream Rab7 consequences of displacement in infected cells not fully traced
  9. 2020 Medium

    Implicated TBC1D5-driven Rab7 cycling in viral entry, with HPV uniquely requiring GTP/GDP cycling for retromer disassembly and retrograde delivery.

    Evidence Monobody inhibition of TBC1D5, dominant Rab7 mutants, imaging, and infection assays

    PMID:32521275

    Open questions at the time
    • Direct demonstration of TBC1D5 GAP turnover on HPV-containing endosomes limited to inhibition data
    • Single-lab study
  10. 2020 Medium

    Identified TBC1D5 as a target recruited to Coxiella vacuoles via a bacterial kinase, supporting a role in pathogen vacuole development.

    Evidence Co-IP/pull-down, co-localization imaging, and siRNA depletion with CCV morphology readout

    PMID:32303638

    Open questions at the time
    • Whether CstK modifies TBC1D5 enzymatically not established
    • Mechanistic link to Rab7 activity at the CCV unresolved
  11. 2021 Low

    Correlated reduced TBC1D5 in ischemic cardiomyocytes with blocked Rab7 cycling and impaired retrograde transport and cathepsin trafficking.

    Evidence Ischemia/hypoxia cell model with Western blot, microtubule-binding, and cathepsin trafficking assays

    PMID:35004909

    Open questions at the time
    • Largely correlative with limited mechanistic depth
    • Causality of TBC1D5 loss not established by rescue
  12. 2022 Medium

    Showed in vivo that TBC1D5 constrains synaptic growth by limiting BMP receptor levels through Rab7 and retromer.

    Evidence Drosophila loss-of-function genetics, transgenic rescue, EM, and BMP signaling reporters

    PMID:36473687

    Open questions at the time
    • Mechanism by which Rab7/retromer set Wit receptor abundance not detailed
    • Functional link to Rab6 only partially defined
  13. 2023 Medium

    Established that phagophores capture retromer–TBC1D5 endosomes for bulk degradation in an MTORC1/autophagy-controlled, retromer-binding-dependent manner.

    Evidence MTOR inhibition, TBC1D5 LIR- and retromer-binding mutants, and cargo trafficking assays

    PMID:37938196

    Open questions at the time
    • Distinguishing retromer-binding requirement from LIR/dephosphorylation incompletely resolved
    • Single-lab study
  14. 2024 Medium

    Showed SARS-CoV-2 ORF3a–Vps39 sequesters TBC1D5 and displaces Rab7, hyperactivating Rab7 and disrupting CI-M6PR retrieval and lysosomal hydrolase transport.

    Evidence Co-IP, dominant-negative Rab7 rescue of viral replication, imaging, and ORF3a variant studies

    PMID:38448435

    Open questions at the time
    • Direct effect on TBC1D5 catalytic cycle not biochemically isolated
    • Single-study mechanism
  15. 2024 Medium

    Placed TBC1D5 as the downstream effector of pH-dependent Rab7 regulation, inhibited by NHE6-mediated proton signaling at low endosomal pH.

    Evidence Co-IP of NHE6–TBC1D5–Rab7 complex, pH-dependent GAP assay, and epistatic knockdown in NHE6-null neurons (preprint)

    PMID:bio_10.1101_2024.12.09.627558

    Open questions at the time
    • Preprint status limits confidence
    • Structural basis of pH-dependent TBC1D5 inhibition not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple inputs converging on TBC1D5 — retromer docking, LIR-mediated autophagic capture, pH signaling, and phosphoregulation — are integrated to set Rab7 activity at distinct compartments remains unresolved.
  • No unified model of how competing recruitment cues are prioritized
  • Catalytic state of TBC1D5 on Rab7 not captured structurally
  • In vivo mammalian phenotypes of TBC1D5 loss largely uncharacterized in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 3 GO:0005764 lysosome 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-9612973 Autophagy 4 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9609507 Protein localization 3
Partners
AP2ATG9NHE6RAB7ARAB7BULK1VPS29VPS35
Complex memberships
retromer (VPS35/VPS29/VPS26)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 TBC1D5 is a Rab-GAP family protein that interacts with the retromer cargo-selective VPS35/VPS29/VPS26 subcomplex, negatively regulates its recruitment to endosomal membranes, and causes Rab7 to dissociate from the membrane, thereby acting as an inhibitor of retromer membrane association. Co-immunoprecipitation, membrane fractionation, dominant-negative Rab7 mutant analysis, fluorescence microscopy Journal of cell science High 19531583
2016 Crystal structure of the TBC1D5 GAP domain bound to VPS29 shows that a loop from TBC1D5 inserts into a conserved hydrophobic pocket on VPS29 opposite the VPS29-VPS35 interface; a distinct loop of the GAP domain may additionally contact VPS35. Loss of TBC1D5 causes defective retromer-dependent receptor trafficking. X-ray crystallography, biochemical binding assays, site-directed mutagenesis, cell-based trafficking assays Nature communications High 27827364
2014 TBC1D5 associates with ATG9, the active ULK1 complex, clathrin, and the AP2 complex during autophagy. Depletion of TBC1D5 causes missorting of ATG9 to late endosomes upon autophagy activation, and inhibition of clathrin-mediated endocytosis or AP2 depletion alters ATG9 trafficking and its association with TBC1D5. Co-immunoprecipitation, siRNA depletion, fluorescence microscopy, autophagy induction assays EMBO reports High 24603492
2017 Retromer and its associated GAP TBC1D5 maintain Rab7 activity and localization across multiple compartments (late endosomes, lysosomes, ER, TGN, mitochondria). Loss of TBC1D5 or retromer leads to hyperactivated Rab7 that expands over the entire lysosomal domain, depletes the inactive Rab7 pool on endomembranes, misroutes ATG9a, and impairs autophagosome formation around damaged mitochondria during Parkin-mediated mitophagy. siRNA depletion, live-cell fluorescence imaging, FRAP, autophagy/mitophagy assays, flow cytometry The EMBO journal High 29158324
2017 During metabolic stress, TBC1D5 is sequestered onto LC3+ autophagic compartments via its LIR motif, relieving its inhibitory interaction with the retromer complex; this enables retromer recruitment to endosomal membranes and GLUT1 plasma membrane translocation. In autophagy-deficient cells, TBC1D5 inhibitory interactions with retromer are maintained, causing GLUT1 missorting to endolysosomes; TBC1D5 depletion in autophagy-deficient cells rescues retromer recruitment and GLUT1 surface recycling. Autophagy induction/inhibition, TBC1D5 depletion and rescue experiments, cell surface biotinylation, fluorescence microscopy, Co-immunoprecipitation Molecular cell High 28602638
2018 TBC1D5 is a GAP for Rab7b (in addition to Rab7a): it localizes to Rab7b-positive vesicles, physically interacts with Rab7b, and displays GAP activity toward Rab7b in vitro; this GAP activity is further increased by retromer proteins. Loss of TBC1D5 reduces the number of CI-MPR- and sortilin-positive vesicles, similarly to constitutively active Rab7b. siRNA screen with phenotypic readout, Co-immunoprecipitation, in vitro GAP activity assay, fluorescence microscopy, cell-based trafficking assay Journal of cell science High 30111580
2018 Pharmacological inhibition of TBC1D5 enhances Rab7a activation and leads to a gain-of-function for the retromer complex, improving endosomal sorting. Chemical inhibition, Rab7a activation assay (RILP pulldown), retromer recruitment imaging Journal of cell science Medium 29777037
2017 The Legionella pneumophila effector RidL competes with TBC1D5 for binding to the Vps29 retromer subunit via a protruding β-hairpin (Ile170 in RidL / Leu152 in Vps29), thereby displacing TBC1D5 from the retromer and from Legionella-containing vacuoles; TBC1D5 displacement promotes intracellular bacterial replication. Crystal structure of RidL-Vps29 complex, site-directed mutagenesis, Co-immunoprecipitation in eukaryotic cells, in vitro binding assay, intracellular replication assay Nature communications High 29146912
2020 During human papillomavirus entry, binding of retromer to the HPV L2 capsid protein recruits TBC1D5 to the retromer at the endosomal membrane; TBC1D5 then stimulates Rab7-GTP hydrolysis to drive retromer disassembly from HPV and delivery of HPV to the retrograde pathway. HPV trafficking requires cycling between GTP- and GDP-bound Rab7, whereas cellular retromer cargos (CIMPR, DMT1-II) require only GTP-bound Rab7. Artificial protein selection against TBC1D5 (monobody inhibition), dominant-negative and constitutively active Rab7 mutants, fluorescence microscopy, infection assays Cell reports Medium 32521275
2020 The Coxiella burnetii secreted kinase CstK physically interacts with host TBC1D5, co-localizes with it in non-infected cells, and TBC1D5 is recruited to Coxiella-containing vacuoles (CCVs) during infection; TBC1D5 depletion significantly impairs CCV development. Protein-protein interaction assay (co-immunoprecipitation/pull-down), co-localization by fluorescence microscopy, siRNA depletion with CCV morphology readout The Journal of biological chemistry Medium 32303638
2024 SARS-CoV-2 ORF3a, in complex with Vps39, sequesters TBC1D5 and displaces Rab7 from the TBC1D5-Rab7 complex, thereby disrupting the GTP hydrolysis cycle of Rab7 and causing Rab7 hyperactivation. This impairs CI-M6PR retrieval from late endosomes to TGN, disrupts lysosomal hydrolase biosynthetic transport, and reduces tethering of Rab7- and Arl8b-positive compartments. Co-immunoprecipitation, dominant-negative Rab7 mutant rescue of viral replication, fluorescence microscopy, ORF3a variant expression studies Nature communications Medium 38448435
2023 Under nutrient-replete conditions, MTORC1-mediated autophagy inhibition controls the abundance of retromer+ endosomes. Upon autophagy activation (MTOR inhibition or nutrient withdrawal), phagophores capture retromer-TBC1D5 endosomes for bulk destruction; TBC1D5 and its ability to bind retromer (but not its C-terminal LIR motif or nutrient-regulated dephosphorylation) is required for autophagosomal capture of retromer endosomes, leading to lysosomal turnover of recycling cargoes. MTOR inhibition, autophagy induction, TBC1D5 mutant analysis (LIR-mutant, retromer-binding mutant), cargo trafficking assays, fluorescence microscopy Autophagy Medium 37938196
2022 In Drosophila NMJ, TBC1D5 constrains synaptic growth by regulating Rab7 activity; loss of TBC1D5 increases the protein level of the BMP type II receptor Wishful Thinking (Wit) at the NMJ, upregulating BMP signaling. Disruption of TBC1D5 interactions with Rab7 and retromer phenocopies TBC1D5 loss. TBC1D5 is also functionally linked to Rab6 in regulating synaptic growth. Drosophila genetics (loss-of-function mutants, transgenic rescue), electron microscopy, immunofluorescence, BMP signaling reporter assays Journal of genetics and genomics Medium 36473687
2021 In ischemic/hypoxic cardiomyocytes, TBC1D5 is reduced, leading to blockade of the Rab7 membrane cycle; this impedes retromer binding to microtubules and motor proteins, impairing retrograde transport and decreasing CI-MPR levels, which disrupts trafficking of lysosomal cathepsins. Ischemia/hypoxia cell model, Western blot, immunofluorescence, microtubule-binding assay, cathepsin trafficking assay Frontiers in cardiovascular medicine Low 35004909
2024 NHE6-mediated inside-out proton signaling activates Rab7 through potent inactivation of the Rab7 GAP TBC1D5 at decreasing endosomal pH; NHE6 physically interacts with TBC1D5 in a complex with Rab7. Epistatic knockdown of TBC1D5 in NHE6-null neurons rescues Rab7 GTPase cycling and endosome maturation, establishing TBC1D5 as the downstream effector of pH-dependent Rab7 regulation. Co-immunoprecipitation (NHE6-TBC1D5-Rab7 complex), pH-dependent GAP activity assay, NHE6-null mouse neurons, epistatic siRNA knockdown, endosome maturation assay bioRxiv (preprint)preprint Medium bio_10.1101_2024.12.09.627558

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5. Journal of cell science 306 19531583
2017 Control of RAB7 activity and localization through the retromer-TBC1D5 complex enables RAB7-dependent mitophagy. The EMBO journal 163 29158324
2014 TBC1D5 and the AP2 complex regulate ATG9 trafficking and initiation of autophagy. EMBO reports 147 24603492
2017 Autophagy-Dependent Shuttling of TBC1D5 Controls Plasma Membrane Translocation of GLUT1 and Glucose Uptake. Molecular cell 121 28602638
2016 Structural and mechanistic insights into regulation of the retromer coat by TBC1d5. Nature communications 92 27827364
2018 Inhibition of TBC1D5 activates Rab7a and can enhance the function of the retromer cargo-selective complex. Journal of cell science 64 29777037
2017 Structural insights into Legionella RidL-Vps29 retromer subunit interaction reveal displacement of the regulator TBC1D5. Nature communications 42 29146912
2024 SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle. Nature communications 38 38448435
2018 TBC1D5 controls the GTPase cycle of Rab7b. Journal of cell science 38 30111580
2020 TBC1D5-Catalyzed Cycling of Rab7 Is Required for Retromer-Mediated Human Papillomavirus Trafficking during Virus Entry. Cell reports 34 32521275
2020 The secreted protein kinase CstK from Coxiella burnetii influences vacuole development and interacts with the GTPase-activating host protein TBC1D5. The Journal of biological chemistry 13 32303638
2024 Enhancing Rab7 Activity by Inhibiting TBC1D5 Expression Improves Mitophagy in Alzheimer's Disease Models. Journal of Alzheimer's disease : JAD 10 38848175
2023 Autophagy captures the retromer-TBC1D5 complex to inhibit receptor recycling. Autophagy 10 37938196
2024 TBC1D5 reverses the capability of HIF-2α in tumor progression and lipid metabolism in clear cell renal cell carcinoma by regulating the autophagy. Journal of translational medicine 7 38419050
2020 miR-10 involved in salinity-induced stress responses and targets TBC1D5 in the sea cucumber, Apostichopus japonicas. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 7 31904427
2012 Integration of H-2Z1, a somatosensory cortex-expressed transgene, interferes with the expression of the Satb1 and Tbc1d5 flanking genes and affects the differentiation of a subset of cortical interneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 7 22623674
2022 GTPase-activating protein TBC1D5 coordinates with retromer to constrain synaptic growth by inhibiting BMP signaling. Journal of genetics and genomics = Yi chuan xue bao 6 36473687
2021 Impaired Retrograde Transport Due to Lack of TBC1D5 Contributes to the Trafficking Defect of Lysosomal Cathepsins in Ischemic/Hypoxic Cardiomyocytes. Frontiers in cardiovascular medicine 0 35004909
2020 Gender-Discordant Monochorionic-Diamniotic Twins Both With 45,X/46,X, Idic(Y) Mosaicism and a Novel Deletion Within the TBC1D5 Gene. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 0 32364436

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