TTC36

TTC36 (HBP21) is a TPR-motif chaperone protein that stabilizes client proteins by preventing their phosphorylation-dependent ubiquitination, with documented roles in hepatic amino-acid catabolism and tumor signaling (PMID:31537781, PMID:41208883). Its three tandem TPR motifs bind the C-terminal EEVD/PTIEEVD residues of HSP70, defining a canonical co-chaperone binding mode (PMID:18587674). In hepatocytes, TTC36 associates with HPD and excludes the kinase STK33, blocking STK33-mediated phosphorylation of HPD at T382; loss of this phosphorylation prevents recruitment of the FHA-domain E3 adaptor PELI1 and the resulting polyubiquitylation and proteasomal degradation of HPD, so that Ttc36 deficiency in mice causes HPD loss, tyrosinemia, hippocampal neuronal damage, and memory deficits (PMID:31537781). TTC36 similarly stabilizes YBX3 by masking its K311/K350 ubiquitination sites, and the stabilized YBX3 binds the CACAUC motif in the SPRED1 3'UTR to enhance SPRED1 mRNA stability and suppress Ras/MAPK signaling (PMID:41208883). It also promotes c-Myc accumulation by disrupting the SET–PPP2R1A interaction to suppress PP2A activity, thereby preserving stabilizing c-Myc phosphorylation and blocking FBXW7-mediated degradation (PMID:40274799). Through its HSP70 interaction TTC36 inhibits the HSP70–Bax association, promoting Bax mitochondrial translocation, cytochrome c release, and apoptosis under stress (PMID:26246424). TTC36 is expressed in liver and kidney and localizes specifically to renal proximal tubules (PMID:27826126).

1. 2008 Medium

   Established the physical basis for TTC36 acting as a co-chaperone by defining how it engages HSP70, the first molecular interaction assigned to the protein.

   Evidence Yeast two-hybrid and GST pull-down with HSP70 truncation/substitution mutants mapping the interaction to HSP70's C-terminal EEVD/PTIEEVD residues via TTC36's three TPR motifs

   PMID:18587674

   Open questions at the time

   • Functional consequence of the HSP70 interaction not addressed
   • Single-lab in vitro mapping without cellular validation
2. 2015 Medium

   Connected the HSP70 interaction to a cellular outcome, showing TTC36 modulates apoptosis by interfering with HSP70's anti-apoptotic sequestration of Bax.

   Evidence HBP21 transfection in HCC cells with Co-IP of HSP70–Bax, subcellular fractionation for Bax translocation, and cytochrome c release/apoptosis assays

   PMID:26246424

   Open questions at the time

   • Whether the HSP70 TPR interaction is mechanistically required for Bax displacement not directly tested
   • Single-cell-line, overexpression-based
3. 2016 Medium

   Defined the tissue and subcellular context of TTC36 expression, anchoring its function to renal proximal tubules and liver.

   Evidence Immunofluorescence in mouse tissues with co-localization against proximal (LTL) and distal (Calbindin-D28k) tubule markers across developmental stages

   PMID:27826126

   Open questions at the time

   • Localization is descriptive and not linked to a molecular function
   • No subcellular compartment resolved within tubule cells
4. 2019 High

   Provided the definitive in vivo mechanism: TTC36 protects HPD from a kinase/E3-ligase degradation axis, establishing a physiological role in tyrosine catabolism.

   Evidence Co-IP, in vitro kinase assay, T382 phospho-site mutagenesis, ubiquitylation assay, and Ttc36-knockout mouse with tyrosinemia and neurological phenotype

   PMID:31537781

   Open questions at the time

   • Whether the same STK33/PELI1 axis operates on other clients unknown
   • Structural detail of HPD–TTC36 binding not resolved
5. 2021 Low

   Implicated TTC36 as a negative regulator of Wnt/β-catenin signaling in gastric carcinoma, suggesting a tumor-suppressive role.

   Evidence Lentiviral overexpression/knockdown in GC cells with Western blot for β-catenin/TCF4/c-jun/pAKT and XAV939 pharmacological rescue

   PMID:33854620

   Open questions at the time

   • No direct biochemical interaction between TTC36 and Wnt components demonstrated
   • Mechanism inferred pharmacologically
   • Single lab
6. 2024 Low

   Extended TTC36's protein-stabilizing role to inflammation, indicating it suppresses NF-κB signaling in renal tubular cells.

   Evidence Lentiviral overexpression in HK2 cells with cycloheximide chase, MG132 reversal of IκBα stabilization, and cytokine/apoptosis/proliferation readouts

   PMID:39215665

   Open questions at the time

   • No direct TTC36–IκBα interaction shown
   • Overexpression-only in a single cell line
7. 2025 Medium

   Resolved two parallel client-stabilization mechanisms in hepatocellular carcinoma — masking YBX3 ubiquitination sites and disrupting the SET–PP2A interaction to control c-Myc — linking TTC36 to Ras/MAPK suppression and to sorafenib resistance.

   Evidence MS, RNA pulldown, luciferase, K311/K350 mutagenesis, in vivo tumor models (YBX3 axis); Co-IP, PP2A activity, c-Myc S62/T58 phospho and ubiquitination assays with inhibitor rescue (c-Myc axis)

   PMID:40274799 PMID:41208883

   Open questions at the time

   • The two axes are characterized separately; their integration in the same cells unclear
   • Single-lab, not independently replicated
   • Direct binding interfaces not structurally resolved
8. 2025 Low

   Linked TTC36 to macrophage polarization and PI3K/AKT signaling in a sepsis-associated renal injury context.

   Evidence Lentiviral overexpression/knockdown in RAW264.7 macrophages with flow cytometry, PI3K inhibitor/activator rescue, and a CLP rat model

   PMID:40757051

   Open questions at the time

   • No direct TTC36–PI3K biochemical interaction
   • Predominantly phenotypic readouts
   • Single lab

• It remains unknown whether TTC36's diverse client interactions (HPD, YBX3, SET/PP2A, IκBα) share a common TPR-mediated recognition mechanism or reflect distinct binding modes.
• No structural model of TTC36 bound to any client
• Whether HSP70 co-chaperone activity underlies all client-stabilization events untested
• Generality of the kinase/E3-ligase shielding mechanism across clients unestablished