The Nuclear Envelope Proteins Esc1 and Mps3 Differentially Impact Sterol Gradients in Budding Yeast
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Bibliographic record
Abstract
ABSTRACT The metabolically stable lysolipid analogue edelfosine is an antitumor/antiparasitic drug proposed to act by disrupting lipid rafts and reducing the accessible sterol pool at the plasma membrane (PM). Once internalized, edelfosine also induces deformation of the nuclear envelope (NE) and disrupts telomere clustering in yeast. In this study we investigate the impact that NE‐chromatin‐anchoring pathways have on PM and NE/ER sterol homeostasis. Cells lacking Sir4 ( sir4 Δ) of the Silent Information Regulator histone deacetylase complex are resistant to edelfosine despite NE deformation induced by the drug. Using live fluorescence microscopy, we show herein that in sir4 Δ yeast sterols remain accessible at the PM and redistribute from the PM of daughter cells to the PM of mother cells in response to edelfosine. Since Sir4 is the scaffold component of the SIR complex that mediates telomere anchoring to the NE, we questioned if its interactors at the NE, Esc1, and Mps3, could also impact sterol mobilization in response to edelfosine. Cells lacking Esc1 mimicked the phenotypes of sir4 Δ yeast in response to edelfosine. Unlike sir4 Δ and esc1 Δ yeast, cells carrying a truncated Mps3 unable to bind Sir4, mps3 Δ65‐145, displayed aberrant NE morphology, intracellular sterol punctate and sensitivity to edelfosine. Furthermore, significative differences in squalene to sterol esters ratios between esc1 Δ and mps3 Δ65‐145 mutants were found. Altogether these results support a differential contribution of Esc1 and Mps3 to sterol homeostasis and establishment of its intracellular gradient. The Sir4‐Esc1 interaction sensitizes cells to lysolipid toxicity and sterol transport from the PM, while Mps3 has a stronger influence on silencing and sterol retention capacity at the PM.
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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