Exploring the differential localization of protein kinase A isoforms in <i>Candida albicans</i>
Bibliographic record
Abstract
ABSTRACT The cAMP-dependent protein kinase A (PKA) plays important roles in a wide range of biological processes in eukaryotic organisms. In the fungal pathogen Candida albicans , PKA is a critical regulator of morphological transitions, which are a key virulence trait. PKA is composed of two catalytic isoforms, Tpk1 and Tpk2, which are often thought to act together in a complex with the regulatory subunit Bcy1. Although Tpk1 and Tpk2 have some redundant functions, they also have distinct cellular functions for which the mechanistic underpinnings remain largely elusive. Here, we constructed functional GFP-tagged fusion proteins for Tpk1, Tpk2, and Bcy1 to explore the localization of PKA isoforms. We observed that the PKA holoenzyme is mainly found in the cytoplasm, as Bcy1 is always excluded from the nucleus. Under glucose-replete conditions, both Tpk1 and Tpk2 translocate into the nucleus from the cytosol. In the presence of glycerol, Tpk1 resides in the cytosol, whereas Tpk2 and Bcy1 become enriched on the vacuolar membrane. As the C-terminal domains of Tpk are highly homologous, we investigated the localization and function of hybrid Tpk proteins with exchanged N-terminal domains. We found the catalytic C-terminus of Tpk1 is required for morphogenesis in solid medium, whereas the C-terminus of Tpk2 is critical for filamentation in liquid. Interestingly, the N-terminus of Tpk2 drives its localization to the vacuolar membrane. Our work highlights environmentally contingent localization patterns for the PKA subunits and suggests that the nuclear localization of Tpk is not sufficient to induce the filamentation program in a leading fungal pathogen of humans. IMPORTANCE Fungal pathogens have a devastating impact on human health worldwide. They infect billions of people and kill more than 2.5 million per year. Candida albicans is a leading human fungal pathogen responsible for causing life-threatening systemic disease in immunocompromised individuals. A key virulence trait in C. albicans is the ability to switch between yeast and filamentous forms. The conserved protein kinase A (PKA) regulates diverse functions in the cell, including growth and filamentation. Although PKA has been studied in C. albicans for decades, the subcellular localization of PKA has not been thoroughly investigated. Here, we constructed functional GFP-tagged PKA subunits to explore their localization. We identified differential localization patterns for the PKA subunits that are carbon-source dependent and report that these proteins localize into foci in response to diverse environmental stresses. These findings further our understanding of a critical regulator of growth and virulence in C. albicans .
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How this classification was reachedexpand
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".