CO 2 Signaling through the Ptc2-Ssn3 Axis Governs Sustained Hyphal Development of Candida albicans by Reducing Ume6 Phosphorylation and Degradation

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 CO 2 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 CO 2 and O 2 , respectively. To uncover the CO 2 signaling pathway that regulates Ume6 stability, we performed genetic screens for mutants unable to respond to CO 2 for sustained filamentation. We find that the type 2C protein phosphatase Ptc2 is specifically required for CO 2 -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 CO 2 Furthermore, we find that Ssn3 is dephosphorylated in 5% CO 2 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 CO 2 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, CO 2 is a key determinant involved in fundamental biological processes, including growth, morphology, and virulence. In the pathogenic fungus Candida albicans , high CO 2 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 CO 2 Here we report that a signal transduction system mediated by a phosphatase-kinase pair controls CO 2 -responsive Ume6 phosphorylation and stability that in turn dictate hyphal elongation. Our results unravel a new regulatory mechanism of CO 2 signaling in fungi.