TBC1D14

TBC1D14 is a TBC-domain-containing regulator of autophagosome biogenesis that controls membrane delivery from recycling endosomes and ATG9 trafficking through the early secretory pathway. TBC1D14 resides on RAB11-positive recycling endosomes where it binds GTP-loaded RAB11 (without GAP activity toward RAB11) and colocalizes with the autophagy kinase ULK1; upon amino acid starvation it relocalizes to the Golgi, releasing recycling-endosome-derived membranes for autophagosome formation (PMID:22613832, PMID:22874560). Through its N-terminal region TBC1D14 also engages the TRAPPIII tethering/GEF complex (via TRAPPC8), and this interaction independently maintains ATG9 cycling required for autophagy initiation by promoting RAB1 activation (PMID:26711178). Loss-of-function mutation in mouse Tbc1d14 causes embryonic lethality, indicating an essential developmental role (PMID:21118569).

1. 2010 Medium

   A forward genetic screen established that TBC1D14 is essential for mouse embryonic development, raising the question of what cellular process it controls.

   Evidence ENU mutagenesis screen with positional cloning in mouse embryos

   PMID:21118569

   Open questions at the time

   • Molecular mechanism underlying embryonic lethality not resolved
   • Whether the developmental requirement reflects autophagy, membrane trafficking, or another process is unknown
2. 2012 High

   Identification of TBC1D14 as a RAB11- and ULK1-interacting protein on recycling endosomes established that recycling endosomal membranes serve as a membrane source for autophagosome biogenesis, with TBC1D14 acting as a negative regulator by sequestering these membranes when overexpressed and relocalizing to the Golgi upon starvation to permit their release.

   Evidence Co-immunoprecipitation, live-cell imaging, transferrin recycling assays, RAB11 epistasis, and starvation-induced relocalization in mammalian cell lines

   PMID:22613832 PMID:22874560

   Open questions at the time

   • How starvation triggers TBC1D14 relocalization from recycling endosomes to the Golgi is unknown
   • Whether TBC1D14 possesses GAP activity toward any other Rab remains untested
   • Endogenous loss-of-function phenotype in mammalian cells not characterized at this stage
3. 2015 High

   Discovery that TBC1D14 binds the TRAPPIII complex through its N-terminal 103-amino-acid region revealed a ULK1-independent axis by which TBC1D14 maintains ATG9 trafficking and RAB1 activation required for autophagy initiation.

   Evidence Mass spectrometry interactomics, domain-mapping overexpression, ATG9 trafficking assays, knockdown epistasis, and RAB1 activation assays

   PMID:26711178

   Open questions at the time

   • Whether TRAPPIII binding and RAB11 binding are coordinated or represent separable pools of TBC1D14 is unresolved
   • Structural basis of TBC1D14–TRAPPIII interaction is unknown
   • How TBC1D14 regulates the RAB1 activation step mechanistically is not defined
4. 2020 Medium

   Validation that miR-146b-5p directly targets TBC1D14 mRNA provided a post-transcriptional regulatory input linking innate immune signaling to TBC1D14-dependent autophagy.

   Evidence Luciferase reporter assay confirming direct 3′-UTR targeting in Brucella-infected macrophages

   PMID:32051823

   Open questions at the time

   • Functional consequence of miR-146b-5p–mediated TBC1D14 reduction on autophagy flux is indirect
   • Relevance beyond Brucella infection context not tested
5. 2022 Medium

   TBC1D14 was shown to suppress autophagy in head-and-neck squamous cell carcinoma cells through negative regulation of MAEA expression, extending TBC1D14's autophagy-regulatory role to a cancer context.

   Evidence Mass spectrometry, western blot, immunofluorescence, TEM, rescue experiments, and in vivo mouse model in HNSCC

   PMID:35342354

   Open questions at the time

   • Mechanism by which TBC1D14 regulates MAEA expression is not defined
   • Single-lab finding lacking independent replication
   • Whether this axis operates outside HNSCC is unknown
6. 2025 Medium

   TBC1D14 was found to promote TRIM25-mediated K63-linked ubiquitination and degradation of DDX31, thereby suppressing ribosome biogenesis and epithelial–mesenchymal transition in HNSCC, revealing a function beyond canonical autophagy regulation.

   Evidence Proteomic profiling, co-immunoprecipitation, ubiquitination assays, knockdown/overexpression with in vivo metastasis model

   PMID:40784392

   Open questions at the time

   • Single-lab finding not independently replicated
   • Whether TBC1D14's role in DDX31 degradation is linked to its recycling-endosome or TRAPPIII functions is unknown
   • Direct structural or biochemical basis for TBC1D14–TRIM25 cooperation is not established

• Key open questions include the signal that triggers TBC1D14 relocalization from recycling endosomes to the Golgi upon starvation, whether TBC1D14 possesses GAP activity toward any Rab family member, and how its autophagy-regulatory and ribosome-biogenesis-regulatory functions are coordinated.
• No structural model of TBC1D14 exists
• Whether TBC1D14 has catalytically active GAP function toward any Rab is unresolved
• Mechanism linking starvation sensing to TBC1D14 relocalization is unknown