title: Regulation of theCandida albicansHypha-Inducing Transcription Factor Ume6 by the CDK1 Cyclins Cln3 and Hgc1.
abstract: The ability to switch between proliferation as yeast cells and development into hyphae is a hallmark ofCandida albicans. The switch to hyphal morphogenesis depends on external inducing conditions, but its efficiency is augmented in stationary-phase cells. Ume6, a transcription factor that is itself transcriptionally induced under hypha-promoting conditions, is both necessary and sufficient for hyphal morphogenesis. We found that Ume6 is regulated posttranslationally 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 SCFCDC4ubiquitin ligase. SinceHGC1is a key transcriptional target of Ume6, this results in a negative-feedback loop between Hgc1 and Ume6. In addition, we found that Cln3, a G1cyclin that is essential for cell cycle progression and yeast proliferation, suppresses hyphal morphogenesis and that Cln3 suppresses Ume6 activity both in the heterologousSaccharomyces cerevisiaesystem and inC. albicansitself. This activity of Cln3 may provide the basis for the antagonistic relationship between yeast proliferation and hyphal development inC. albicans.IMPORTANCEThe yeast to hypha (mold) morphogenetic switch ofCandida albicansplays 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. The G1cyclin Cln3, an essential promoter of yeast proliferation, was found to suppress hyphal induction. Suppression of hyphal induction is 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 ofC. albicansas individual yeast cells and development into extended hyphae, a switch that may preface the proliferation/differentiation switch in multicellular organisms.
authors.affiliation: Department of Molecular Microbiology, B. Rappaport Faculty of Medicine, Technion-I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
authors.forename: Sigal
authors.initials: S
authors.lastname: Mendelsohn
authors.affiliation: Department of Molecular Microbiology, B. Rappaport Faculty of Medicine, Technion-I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
authors.forename: Mariel
authors.initials: M
authors.lastname: Pinsky
authors.affiliation: Department of Molecular Microbiology, B. Rappaport Faculty of Medicine, Technion-I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
authors.forename: Ziva
authors.initials: Z
authors.lastname: Weissman
authors.affiliation: Department of Molecular Microbiology, B. Rappaport Faculty of Medicine, Technion-I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
authors.forename: Daniel
authors.identifier: 0000-0002-5062-2735
authors.initials: D
authors.lastname: Kornitzer
keywords: Candida albicans; Cdc4; Cln3; Hgc1; SCF; morphogenesis