An essential role for ClC-4 in transferrin receptor function revealed in studies of fibroblasts derived from <i>Clcn4</i>-null mice
Bibliographic record
Abstract
ClC-4 is closely related to ClC-5, a member of the ClC family of transporters and channels. Unlike ClC-5, for which a role in the regulation of endosomal function was well established, the cellular function of ClC-4 was uncertain. In the present study, we tested for a specific role for ClC-4 in recycling endosomes by comparing transferrin (Tfn) receptor function in primary cell lines generated from ClC-4-null mice and their wild-type siblings. We found that endosomal pH is relatively alkaline and receptor-mediated uptake of Tfn is reduced in ClC-4-null fibroblasts. Surprisingly, this reduction in Tfn uptake occurs, despite a minor increase in the total surface expression of the Tfn receptor in ClC-4-null fibroblasts. As impaired Tfn uptake by ClC-4-null fibroblasts could be rescued to wild-type levels by addition of the iron chelator: desoxiferramine, the primary defect in these cells is related to the failure of iron to dissociate from Tfn, a pH-dependent event in endosomes that precedes the dissociation of Tfn from its receptor at the cell surface. Interestingly, ClC-4 depletion had no effect on epidermal growth factor receptor (EGFR) trafficking to lysosomes for degradation pointing to its specific role in recycling endosomes. These observations provide direct evidence supporting an essential role for ClC-4 in the modulation of Tfn receptor accessibility at the cell surface through its role in endosomal acidification.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".