Functional insight into cyclin-dependent kinase (CDK)7 via chemical inhibition of the priority fungal pathogen <i>Cryptococcus neoformans</i>
Notice bibliographique
Résumé
ABSTRACT Cyclin-dependent kinase (CDK)7 regulates the cell cycle and transcription in higher eukaryotes, but its function and the antifungal potential of CDK7 inhibitors remain unexplored in fungal pathogens. CDK7 inhibitors were identified to probe CDK7 function in the priority fungal pathogen, Cryptococcus neoformans ( Cn ). The CDK7 ortholog in Cn was tagged with mNeonGreen and shown to form a nuclear-localized, CDK-activating kinase (CAK) complex with cyclin H and assembly factor Mat1. The pulled-down CAK complex was demonstrated to be active and was used to identify several human CDK7 inhibitors that also inhibit Cn CDK7 enzyme activity. In addition to inhibiting Cn CDK7 enzyme activity, the compound mevociclib (SY-1365) most significantly inhibited fungal growth and was deployed to probe Cn CDK7 function using multi-omics analysis, flow cytometry, and Western blotting, with roles in transcription via RNA polymerase II phosphorylation, mRNA splicing, and progression through G 2 /M of the cell cycle identified. Inhibition of CDK7 also suppressed MAP kinase (Hog1) signaling. Notably, compound SY-1365 and related inhibitors synergized with licensed, membrane-targeting antifungals at low micromolar concentrations against both C. neoformans and Cryptococcus gattii . Our findings establish SY-1365 as a powerful chemical probe to define CDK7 function in Cn and suggest that its role more closely resembles that in human cells than in model fungi. Furthermore, given that CDK7 inhibitors are used in oncology, our findings identify CDK7 inhibitors as promising antifungal candidates for combination therapy with licensed antifungals, with the potential to overcome current challenges associated with toxicity and antifungal resistance. IMPORTANCE Cn , a basidiomycete causing meningoencephalitis with 40%–60% mortality, was recently assigned as a “critical” priority pathogen by the World Health Organization. Cn commonly affects AIDS patients, organ transplant recipients, and individuals with hematological malignancies, yet current treatments are limited by toxicity or resistance due to prolonged therapy. Given that CDK7 inhibitors kill leukemia cells, and Cn proliferation in host tissues mimics tumor-like growth, we investigated whether their utility as anticancer agents extends to antifungal activity and elucidation of CDK7 function in Cn . Use of SY-1365, which was both antifungal and CnCDK7 inhibitory, identified roles for CnCDK7 in all stages of transcription, mRNA splicing, and cell cycle regulation. The antifungal activity of SY-1365 was also markedly enhanced in combination with membrane-targeting antifungals. Together, our findings highlight CDK7 inhibitors as valuable tools to study CDK7 function in Cn and as potentially promising antifungals in combination with licensed antifungals.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».