Hsp70 and DNAJA2 limit CFTR levels through degradation
Bibliographic record
Abstract
Cystic Fibrosis is caused by mutations in the CFTR anion channel, many of which cause its misfolding and degradation. CFTR folding depends on the Hsc70 and Hsp70 chaperones and their co-chaperone DNAJA1, but Hsc70/Hsp70 is also involved in CFTR degradation. Here, we address how these opposing functions are balanced. DNAJA2 and DNAJA1 were both important for CFTR folding, however overexpressing DNAJA2 but not DNAJA1 enhanced CFTR degradation at the endoplasmic reticulum by Hsc70/Hsp70 and the E3 ubiquitin ligase CHIP. Excess Hsp70 also promoted CFTR degradation, but this occurred through the lysosomal pathway and required CHIP but not complex formation with HOP and Hsp90. Notably, the Hsp70 inhibitor MKT077 enhanced levels of mature CFTR and the most common disease variant ΔF508-CFTR, by slowing turnover and allowing delayed maturation, respectively. MKT077 also boosted the channel activity of ΔF508-CFTR when combined with the corrector compound VX809. Thus, the Hsp70 system is the major determinant of CFTR degradation, and its modulation can partially relieve the misfolding phenotype.
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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 | 0.001 |
| 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".