TBC1D9B

TBC1D9B is a TBC-domain GTPase-activating protein (GAP) that regulates membrane trafficking by inactivating specific Rab and Arf-like GTPases at endosomal and lysosomal compartments (PMID:25232007, PMID:41832156). Its TBC domain confers bona fide GAP activity toward Rab11a—binding multiple Rab GTPases in a nucleotide-dependent manner but selectively stimulating Rab11a GTP hydrolysis (and Rab8a only at limiting Mg2+)—and it localizes to Rab11a-positive recycling endosomes (PMID:25232007). Through this Rab11a inactivation, TBC1D9B controls Rab11a-dependent traffic: it restrains basolateral-to-apical IgA transcytosis by disrupting the Rab11a–Sec15A effector interaction (PMID:25232007), and downstream of the Cdk5–LMTK1A kinase cascade it limits dendritic spine formation in neurons, where LMTK1A binds TBC1D9B and controls its GAP activity toward Rab11a (PMID:31628178). At lysosomes, TBC1D9B is recruited via a conserved TMEM55B-binding motif into a TMEM55B adaptor platform and via Arl8b to LAMP1-positive membranes (PMID:41314214, PMID:42166252); there it directly binds and inactivates the kinesin-activating GTPase ARL8B to control lysosome positioning, autophagic flux, and adaptive catabolism, with its knockout phenotypes rescued by ARL8 co-depletion (PMID:41832156). TBC1D9B additionally directs LAMP1 and CI-M6PR cargo sorting by suppressing their Rab11a-dependent missorting, supporting pro-cathepsin trafficking and cargo degradation (PMID:42166252), and engages mammalian ATG8/LC3B homologues through a non-canonical interacting domain to promote autophagic flux (PMID:30202024).

1. 2014 High

   Established TBC1D9B's core biochemical identity and substrate specificity, answering whether and which Rab GTPases it inactivates.

   Evidence In vitro GTP hydrolysis and nucleotide-dependent binding assays with active-site mutagenesis, plus colocalization in polarized MDCK cells

   PMID:25232007

   Open questions at the time

   • Physiological relevance of the low-Mg2+ Rab8a activity unresolved
   • Mechanism of TBC1D9B recruitment to recycling endosomes not defined
2. 2014 High

   Connected the GAP biochemistry to a cellular trafficking output by showing TBC1D9B specifically tunes Rab11a-dependent transcytosis and disrupts effector engagement.

   Evidence Reciprocal overexpression/shRNA transcytosis assays with pathway-specific controls, active-Rab11a pulldown, and Rab11a–Sec15A co-IP in MDCK cells

   PMID:25232007

   Open questions at the time

   • Upstream regulators of TBC1D9B activity not identified at this stage
   • Whether other Rab11a effectors besides Sec15A are affected unknown
3. 2018 High

   Extended TBC1D9B's role into autophagy by identifying a non-canonical ATG8/LC3B interaction that promotes autophagic flux.

   Evidence Yeast two-hybrid, in vitro binding with purified proteins, co-IP, colocalization, LC3B turnover and long-lived protein degradation assays

   PMID:30202024

   Open questions at the time

   • Molecular definition of the unique non-LIR interacting domain incomplete
   • Whether the LC3B interaction requires GAP activity not established
4. 2019 High

   Placed TBC1D9B within a defined kinase cascade, showing LMTK1A binds and regulates its Rab11a GAP activity to control dendritic spine density.

   Evidence Reciprocal co-IP, shRNA knockdown in primary neurons and in vivo, spine morphology analysis, Rab11A activity assay

   PMID:31628178

   Open questions at the time

   • Direct phosphorylation site(s) on TBC1D9B not mapped
   • How LMTK1A binding mechanistically modulates GAP activity unclear
5. 2025 High

   Identified a structural basis for TBC1D9B's lysosomal recruitment via a conserved TMEM55B-binding motif independent of phospho-Rabs.

   Evidence Crystal structure of TMEM55B cytosolic domain, co-IP, mass spectrometry, and mutational analysis (peer-reviewed; corroborated by a preprint)

   PMID:40894729 PMID:41314214

   Open questions at the time

   • Functional consequence of the TMEM55B interaction not yet addressed in this study
   • Stoichiometry and other components of the adaptor platform undefined
6. 2025 Medium

   Linked the LMTK1–TBC1D9B–Rab11a cascade to disease-relevant neuronal phenotypes, showing phospho-LMTK1 activates TBC1D9B to suppress Rab11a trafficking and neurite growth.

   Evidence Co-IP, proteomics, point mutagenesis, AAV-mediated LMTK1 knockdown in Alzheimer's disease mouse models, immunofluorescence, electrophysiology

   PMID:41198459

   Open questions at the time

   • Single-lab disease-model evidence
   • Causal contribution of TBC1D9B itself versus upstream LMTK1 not isolated
7. 2026 High

   Revealed a second GAP substrate and the lysosome-positioning function, establishing TBC1D9B as a TMEM55B-anchored negative regulator of ARL8B.

   Evidence Knockout cell lines, lysosome positioning and autophagic flux assays, direct ARL8B-GTP binding, and genetic epistasis (KO rescued by ARL8 co-depletion)

   PMID:41832156

   Open questions at the time

   • Coordination between ARL8B-GAP and Rab11a-GAP activities not integrated
   • Whether TMEM55B recruitment is required for ARL8B inactivation not fully dissected
8. 2026 High

   Defined how Arl8b-recruited TBC1D9B directs lysosomal cargo sorting by suppressing Rab11a-dependent missorting of LAMP1 and CI-M6PR.

   Evidence RUSH trafficking assays, TBC1D9B and Arl8b loss-of-function, CI-M6PR trafficking and cathepsin processing assays

   PMID:42166252

   Open questions at the time

   • How TBC1D9B is dynamically switched between recycling-endosome and lysosome pools unknown
   • Relationship between Arl8b-mediated recruitment and ARL8B inactivation by TBC1D9B not reconciled

• How TBC1D9B's distinct activities—Rab11a GAP at recycling endosomes, ARL8B GAP at lysosomes, and ATG8 engagement—are coordinated and spatially partitioned within a single cell remains unresolved.
• No structure of full-length TBC1D9B or its substrate-engaged GAP domain
• Regulatory logic balancing Rab11a versus ARL8B targeting undefined
• Phosphorylation-based control of substrate choice not characterized