Calcineurin controls the cytokinesis machinery during thermal stress in <i>Cryptococcus deneoformans</i>
Bibliographic record
Abstract
Abstract Calcineurin is a highly conserved phosphatase that plays a central role in sensing calcium and governing transcriptional, post-transcriptional, and post-translational signaling networks. Calcineurin is a heterodimer consisting of a catalytic A subunit and a regulatory B subunit. Through downstream effectors, calcineurin signaling drives myriad responses in different organisms. In the fungal pathogenic Cryptococcus species complex that infects humans, calcineurin governs thermotolerance and is essential for growth at high temperature and pathogenesis. In Cryptococcus deneoformans , the underlying molecular functions of this critical signaling cascade are not well understood. In this study, we conducted a genetic screen and identified genetic changes that suppress the requirement for calcineurin during high-temperature growth. Our results identified two mechanisms that bypass the requirement for calcineurin function. The first mechanism involves segmental aneuploidy via both amplification as well as loss of chromosome fragments. The second mechanism involves dominant amino acid substitution mutations in the genes encoding three proteins, Chs6, Imp2, and Cts1, orthologs of components of the Ingression Progression Complex required for septation and budding in Saccharomyces cerevisiae . Loss of calcineurin activity causes chitin and chitosan accumulation and severe budding defects, whereas suppressor mutations largely restore growth and cytokinesis in the absence of calcineurin. These findings reveal the calcineurin signaling cascade controls a conserved cytokinesis machinery at the mitotic exit network during thermal stress. Significance Statement Cellular responses to external stress conditions involve activation of signaling cascades, which act via effectors to govern key cellular processes. One such signaling cascade involves the phosphatase calcineurin, the conserved target of cyclosporin A and FK506 that governs myriad cellular functions through its substrates. In human fungal pathogens, calcineurin is critical for pathogenicity. Here, we employed a genetic screen to map the functional interactions of this signaling cascade and repeatedly identified mutations in components of a single protein complex, suggesting a focused downstream response. With genetic and biochemical approaches, we established that these proteins play a crucial role in cell division at high temperature enabling cell division and revealing new avenues of research that could identify potential antifungal drug targets.
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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) | 0.000 | 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 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".