Importance of TFEB acetylation in control of its transcriptional activity and lysosomal function in response to histone deacetylase inhibitors
Bibliographic record
Abstract
TFEB (transcription factor EB) is a master regulator of lysosomal biogenesis, function and autophagy. The transcriptional activity of TFEB is mainly controlled by its phosphorylation status mediated by the MTOR (mechanistic target of rapamycin [serine/threonine kinase]) complex 1 (MTORC1). At present, little is known whether other forms of posttranslational modifications (PTMs) such as acetylation also affects is transcriptional activity. In this study, we first observed that a well-established histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) activated lysosomal function in human cancer cells, a process independent of the MTORC1 pathway. Second, SAHA treatment activated TFEB transcriptional activity, as evidenced by increased TFEB luciferase activity and expression of its target genes. Third and more importantly, we observed the enhanced TFEB acetylation in SAHA-treated cells, with identification of 4 acetylation sites. Mutation of these 4 sites markedly diminished TFEB transcriptional activity and lysosomal function induced by SAHA. Finally, we found that TFEB acetylation was functionally implicated in SAHA-mediated autophagy and cell death in cancer cells. Taken together, our results demonstrate that TFEB acetylation is a novel form of PTMs in TFEB that plays an important role in determining its transcriptional activity, lysosomal function and autophagy in cancer cells. ABBREVIATIONS: ACAT1: acetyl-coenzyme A acetyltransferase 1; AHA: L-azidohomoalanine; AO: acidic orange; ATG: autophagy related; CLEAR: Coordinated Lysosomal Expression and Regulation; CQ: chloroquine; CTSB: cathepsin B; HATs: histone acetyltransferases; HDACIs: HDACs inhibitors; HDACs: histone deacetylases; IP: immunoprecipitation; MEFs: mouse embryonic fibroblasts; MS: mass spectrometry; MTOR: mechanistic target of rapamycin (serine/threonine kinase); MTORC1: mechanistic target of rapamycin (serine/threonine kinase) complex 1; PTMs: posttranslational modifications; SAHA: suberoylanilidehydroxamic acid; TFEB: transcription factor EB.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".