CO₂ Signaling through the Ptc2-Ssn3 Axis Governs Sustained Hyphal Development of Candida albicans by Reducing Ume6 Phosphorylation and Degradation

ABSTRACT

Candida albicans is the most common cause of invasive fungal infections in humans. Its ability to sense and adapt to changing carbon dioxide levels is crucial for its pathogenesis. Carbon dioxide promotes hyphal development. The hypha-specific transcription factor Ume6 is rapidly degraded in air, but is stable under physiological CO₂ and hypoxia to sustain hyphal elongation. Here, we show that Ume6 stability is regulated by two parallel E3 ubiquitin ligases, SCF^Grr1 and Ubr1, in response to CO₂ and O₂, respectively. To uncover the CO₂ signaling pathway that regulates Ume6 stability, we performed genetic screens for mutants unable to respond to CO₂ for sustained filamentation. We find that the type 2C protein phosphatase Ptc2 is specifically required for CO₂-induced stabilization of Ume6 and hyphal elongation. In contrast, the cyclin-dependent kinase Ssn3 is found to be required for Ume6 phosphorylation and degradation in atmospheric CO₂. Furthermore, we find that Ssn3 is dephosphorylated in 5% CO₂ in a Ptc2-dependent manner, whereas deletion of PTC2 has no effect on Ssn3 phosphorylation in air. Our study uncovers the Ptc2-Ssn3 axis as a new CO₂ signaling pathway that controls hyphal elongation by regulating Ume6 stability in C. albicans.

IMPORTANCE The capacity to sense and adapt to changing carbon dioxide levels is crucial for all organisms. In fungi, CO₂ is a key determinant involved in fundamental biological processes, including growth, morphology, and virulence. In the pathogenic fungus Candida albicans, high CO₂ is directly sensed by adenylyl cyclase to promote hyphal growth. However, little is known about the mechanism by which hyphal development is maintained in response to physiological levels of CO₂. Here we report that a signal transduction system mediated by a phosphatase-kinase pair controls CO₂-responsive Ume6 phosphorylation and stability that in turn dictate hyphal elongation. Our results unravel a new regulatory mechanism of CO₂ signaling in fungi.