Posttranslational modifications of the DUX4 protein impact toxic function
Bibliographic record
Abstract
ABSTRACT Objective Facioscapulohumeral muscular dystrophy (FSHD) is caused by abnormal de-repression of the transcription factor DUX4, which is toxic to muscle in vitro and in vivo . While the transcriptional targets of DUX4 are known, the regulation of DUX4 protein and the molecular consequences of this regulation are unclear. Here, we used in vitro models of FSHD to identify and characterize DUX4 posttranslational modifications (PTMs) and their impact on the toxic function of DUX4. Methods DUX4 protein was immunoprecipitated and mass spectrometry performed to identify PTMs. We then extensively characterized DUX4 PTMs and potential enzyme modifiers using mutagenesis, proteomics and biochemical assays in human cell lines and human myoblast cell lines. Results Our in vitro screen of DUX4 PTM mutants identified arginine methyl-null and serine/threonine phosphomimetic mutants that protected cells against DUX4-mediated toxicity and reduced the ability of DUX4 to transactivate downstream gene targets, including FSHD biomarkers. Using additional proteomics and biochemical approaches, we identified protein kinase A (PKA) and a protein arginine methyltransferase (PRMT1) as components of the DUX4 complex. Importantly, over-expression of PRKACA, a catalytic subunit of the PKA holoenzyme, mitigated DUX4 toxicity, while pharmacologic inhibition of PRMT1 protected human myoblasts from DUX4-mediated apoptosis. Interpretation These results demonstrate that DUX4 is regulated by PTMs and that DUX4 PTMs, or associated modifying enzymes, may be druggable targets for FSHD therapy.
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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) | 0.002 | 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".