Yck2 links mitochondrial function and pH homeostasis to cell wall remodeling and antifungal susceptibility in Cryptococcus neoformans

The rise in invasive fungal infections, driven by climate change, antifungal resistance, and immunomodulating therapies, highlights the need for novel therapeutics. The antifungal arsenal is limited, prompting research into the role of specific genes in fungal cellular homeostasis. Deletion of the gene encoding the fungal yeast casein kinase YCK2 in Cryptococcus neoformans results in various impacts, including changes in morphology, drug resistance, metabolism, cell wall, and virulence.

Yck2 has recently emerged as a druggable target, but the mechanisms behind its effects are not well understood. Researchers have discovered that C. neoformans Yck2 is involved in cell wall masking, thermotolerance, general stress response, and drug resistance. Through proximity labeling of Yck2-interacting proteins, they found that Yck2 interacts with proteins functioning in the mitochondria as well as the essential plasma membrane H+ ATPase, Pma1.

The presence of Yck2 in mitochondrial fractions and its impact on mitochondrial function, as evidenced by sensitivity to mitochondrial inhibitors and increased mitochondrial ROS production, provided evidence for Yck2's role in mitochondrial regulation. Additionally, elevated intracellular pH in cells lacking Yck2 was observed, suggesting its involvement in regulating Pma1 activity.

Both mitochondrial function and cellular pH may contribute to cellular signaling, explaining the diverse phenotypes associated with the yck2 deletion mutant. These findings offer insights into the mechanisms by which Yck2 contributes to fungal cellular homeostasis, potentially aiding in the optimization of Yck2 inhibitors for therapeutic purposes.