REGULATION OF THE CANDIDA ALBICANS HYPHA-INDUCING TRANSCRIPTION FACTOR UME6 BY THE CDK1 CYCLINS CLN3 AND HGC1

The yeast to hyphal (mold) morphogenetic switch of Candida albicans plays a role in its virulence, and constitutes a diagnostic trait for this organism, the most prevalent systemic fungal pathogen in industrialized countries. It has long been known that hyphae are most efficiently induced from stationary cultures. Here a molecular basis for this observation is provided. Ume6, a transcription factor that is itself transcriptionally induced under hyphal-promoting conditions, is both necessary and sufficient for hyphal morphogenesis. We find that Ume6 is regulated post-translationally by the cell cycle kinase Cdc28/Cdk1, which reduces Ume6 activity via different mechanisms using different cyclins. Together with the cyclin Hgc1, Cdk1 promotes degradation of Ume6 via the SCF^CDC4 ubiquitin ligase. Since HGC1 is a key transcriptional target of Ume6, this results in a negative feedback loop between Hgc1 and Ume6. In addition we find that Cln3, a G1 cyclin that is essential for cell cycle progression and yeast proliferation, suppresses hyphal morphogenesis, and that Cln3 suppresses Ume6 activity both in the heterologous S. cerevisiae system and in C. albicans itself. This activity of Cln3 may provide the basis for the antagonistic relationship between yeast proliferation and hyphal development in C. albicans: suppression of hyphal induction would be achieved by inhibition of the activity of the central activator of hyphal morphogenesis, the transcription factor Ume6. Thus, levels of Cln3 control the switch between proliferation of C. albicans as individual yeast cells and development into extended hyphae, a switch that may preface the proliferation/differentiation switch in multicellular organisms.