Both Php4 Function and Subcellular Localization Are Regulated by Iron via a Multistep Mechanism Involving the Glutaredoxin Grx4 and the Exportin Crm1
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Bibliographic record
Abstract
In Schizosaccharomyces pombe, the CCAAT-binding factor is a multisubunit complex that contains the proteins Php2, Php3, Php4, and Php5. Under low iron conditions, Php4 acts as a negative regulatory subunit of the CCAAT-binding factor and fosters repression of genes encoding iron-using proteins. Under conditions of iron excess, Php4 expression is turned off by the iron-dependent transcriptional repressor Fep1. In this study, we developed a biological system that allows us to unlink iron-dependent behavior of Php4 protein from its transcriptional regulation by Fep1. Microscopic analyses revealed that a functional GFP-Php4 protein accumulates in the nucleus under conditions of iron starvation. Conversely, in cells undergoing a transition from low to high iron, GFP-Php4 is exported from the nucleus to the cytoplasm. We mapped a leucine-rich nuclear export signal that is necessary for nuclear exclusion of Php4. This latter process was blocked by leptomycin B. By using coimmunoprecipitation analysis, we showed that Php4 and Crm1 physically interact with each other. Although we determined that nuclear retention of Php4 per se is not sufficient to cause a constitutive repression of iron-using genes, we found that deletion of the grx4(+)-encoded glutaredoxin-4 renders Php4 constitutively active and invariably localized in the nucleus. Further analysis by bimolecular fluorescence complementation assay and by two-hybrid assays showed that Php4 and Grx4 are physically associated in vivo. Taken together, our findings indicate that Grx4 and Crm1 are novel components involved in the mechanism by which Php4 is inactivated by iron in a Fep1-independent manner.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 it