Regulation of the Candida albicans Hypha-Inducing Transcription Factor Ume6 by the CDK1 Cyclins Cln3 and Hgc1.

Sigal Mendelsohn,Daniel Kornitzer,Ziva Weissman,Mariel Pinsky

doi:10.1128/msphere.00248-16

Abstract

The ability to switch between proliferation as yeast cells and development into hyphae is a hallmark of Candida 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 SCFCDC4 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 found 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 Saccharomyces 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. IMPORTANCE The yeast to hypha (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. The G1 cyclin 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 of C.albicans as individual yeast cells and development into extended hyphae, a switch that may preface the proliferation/differentiation switch in multicellular organisms.

Highlights

The ability to switch between proliferation as yeast cells and development into hyphae is a hallmark of Candida albicans
Like all known SCFCDC4 substrates, CaUme6 was expected to require phosphorylation in order to be recognized by its ubiquitin ligase
We identify here the Cdc28 cyclin Hgc1 and, in S. cerevisiae, the Cdc28 kinase, together with the G1 cyclins Cln1 and Cln2, as kinases that are required for CaUme6 degradation

Summary

Introduction

The ability to switch between proliferation as yeast cells and development into hyphae is a hallmark of Candida albicans. We found that Cln, a G1 cyclin that is essential for cell cycle progression and yeast proliferation, suppresses hyphal morphogenesis and that Cln suppresses Ume activity both in the heterologous Saccharomyces cerevisiae system and in C. albicans itself. This activity of Cln may provide the basis for the antagonistic relationship between yeast proliferation and hyphal development in C. albicans. C. albicans is able to assume different growth forms, most notably, yeast, hyphal, and pseudohyphal morphologies [2] This ability to switch between different modes of growth and proliferation appears to be important for virulence, based on the reduced pathogenicity in a mouse model of infection by mutants locked in the yeast mode [3, 4]. Additional factors that can influence morphogenetic switching are the quorum-sensing molecules tyrosol, an inducer of hyphal growth [6], and farnesol, a repressor [7]

Methods

Results

Conclusion