Autophagosomes still form after irradiation, but damaged lysosomes cannot clear cargo, sustaining ROS and SASP output.
Curated pathway from expert analysis
flowchart TD
A["mTORC1 Hyperactivation<br/>Nutrient/Growth Signals"]
B["TFEB Phosphorylation<br/>Ser211 by mTORC1"]
C["14-3-3 Sequestration<br/>Cytoplasmic Retention"]
D["Lysosomal Biogenesis<br/>Blocked"]
E["Autophagic Flux<br/>Impaired"]
F["Tau/Amyloid Aggregate<br/>Accumulation"]
G["TFEB Activation<br/>Rapamycin or MCOLN1"]
H["Nuclear TFEB<br/>CLEAR Gene Expression"]
G --> H
H -.->|"rescues"| D
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style H fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for TFEB yet. Search RCSB →
Median TPM across 13 brain regions for TFEB from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TFEB.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF irradiated pericytes exhibit lysosome acidification failure, THEN preventing lysosome acidification with bafilomycin A1 will replicate the radiation-induced senescence phenotype (SA-β-gal positivit | SA-β-gal positive cells ≥40% in 10 Gy irradiated pericytes (vs. <10% in sham); IL-6 concentration in conditioned medium ≥300 pg/mL (vs. <100 pg/mL baseline); in | — no observation — | pending | 0.68 |
| IF primary human brain pericytes are exposed to 10 Gy ionizing radiation, THEN lysosomal pH will increase by ≥0.5 units (deacidification) AND p62/SQSTM1 will accumulate ≥2-fold within 48 hours post-ir | Lysosome pH ≥6.2 (vs. ~5.0 in controls) measured by ratiometric LysoSensor imaging; p62 protein level ≥2-fold elevated by western blot; TFEB remains cytoplasmic | — no observation — | pending | 0.72 |