TBC1D31

TBC1D31 (also called WDR67) is a centrosomal/centriolar scaffold that couples signaling and structural control of the centriole to primary ciliogenesis (PMID:33934390, PMID:40707486). At the centrosome it assembles a complex with the E3 ubiquitin ligase praja2, protein kinase A (PKA), and OFD1; upon GPCR-cAMP stimulation PKA phosphorylates OFD1 at Ser735, driving its praja2-dependent ubiquitin-proteasome degradation, a step required for cilium biogenesis, with loss of TBC1D31 impairing ciliogenesis in cultured cells and in vivo in Medaka (PMID:33934390). Structurally, it localizes to the centriolar A-C linker in a complex with CCDC77 and MIIP that bridges adjacent microtubule triplets at the proximal region to maintain triplet cohesion and regulate centriole duplication (PMID:40707486). Independently, TBC1D31 acts as a Rab22A GTPase-activating protein that suppresses Rab22A-mediated endolysosomal trafficking and degradation of EGFR, sustaining EGFR signaling and promoting hepatocellular carcinoma growth, where its expression is transcriptionally activated by ZSCAN16 (PMID:39206796, PMID:39511655).

1. 2021 High

   Established TBC1D31 as a centrosomal scaffold that links GPCR-cAMP/PKA signaling to controlled OFD1 turnover, answering how a signaling input gates ciliogenesis.

   Evidence Reciprocal Co-IP, centrosome localization, OFD1 S735A phospho-mutant analysis, and in vivo knockdown in Medaka

   PMID:33934390

   Open questions at the time

   • Does not define how TBC1D31 itself is recruited to the centrosome
   • Stoichiometry and assembly order of the praja2/PKA/OFD1 complex unresolved
2. 2021 High

   Demonstrated that TBC1D31 is functionally required for primary ciliogenesis, moving it from a complex component to an essential biogenesis factor.

   Evidence Loss-of-function depletion in cell lines and Medaka with cilium morphology and developmental readouts

   PMID:33934390

   Open questions at the time

   • Whether ciliogenesis defects derive solely from OFD1 dysregulation or other pathways
   • No human disease/genetic link established in the corpus
3. 2024 Medium

   Identified a distinct cytoplasmic role for TBC1D31 as a Rab22A GAP controlling EGFR trafficking, explaining a pro-tumorigenic function separate from its centriolar role.

   Evidence In vitro GAP activity assay, knockdown/overexpression in HCC cells and xenografts, endolysosomal and EGFR degradation assays

   PMID:39206796

   Open questions at the time

   • Single-lab findings without independent replication
   • Relationship between Rab-GAP function and centriolar localization unclear
4. 2024 Medium

   Placed TBC1D31 downstream of a defined transcriptional activator in cancer, showing ZSCAN16 drives its expression to sustain HCC malignancy.

   Evidence ChIP-qPCR, dual-luciferase reporter, lentiviral knockdown/overexpression with functional rescue and xenograft models

   PMID:39511655

   Open questions at the time

   • Whether ZSCAN16-driven expression operates through the Rab22A/EGFR axis specifically not resolved
   • Single-lab evidence
5. 2024 Low

   Associated elevated TBC1D31 with a glycolytic metabolic phenotype in TNBC, broadening its cancer relevance beyond HCC.

   Evidence Transcriptomics/metabolomics correlation and siRNA knockdown with metabolic readouts in TNBC cell lines

   PMID:39231952

   Open questions at the time

   • No mechanistic pathway connecting TBC1D31 to glycolysis established
   • Correlative, single-lab evidence
6. 2025 High

   Resolved the structural role of TBC1D31/WDR67 at the centriolar A-C linker, showing it physically bridges microtubule triplets and supports centriole architecture and duplication.

   Evidence Ultrastructure expansion microscopy, siRNA/KO depletion, co-localization, and co-depletion epistasis with inner scaffold components

   PMID:40707486

   Open questions at the time

   • Molecular basis of triplet bridging by the CCDC77/WDR67/MIIP complex not defined
   • How the A-C linker role integrates with the praja2/PKA/OFD1 signaling function unknown

• It remains unknown how TBC1D31's centriolar structural/ciliogenic functions and its cytoplasmic Rab22A-GAP/EGFR-trafficking role are coordinated within a single protein.
• No structure-function mapping separating GAP, scaffold, and A-C linker activities
• No data on whether the two functions are spatially or temporally exclusive