The NDR/LATS Kinase Cbk1 Controls the Activity of the Transcriptional Regulator Bcr1 during Biofilm Formation in Candida albicans

Pilar Gutiérrez-Escribano,Ute Zeidler,Jaime Correa-Bordes,Andrés Clemente-Blanco,Christophe D'Enfert,Sophie Bachellier-Bassi,Julie Bonhomme,Carlos R Vázquez De Aldana,M Belén Suárez

doi:10.1371/journal.ppat.1002683

Abstract

In nature, many microorganisms form specialized complex, multicellular, surface-attached communities called biofilms. These communities play critical roles in microbial pathogenesis. The fungal pathogen Candida albicans is associated with catheter-based infections due to its ability to establish biofilms. The transcription factor Bcr1 is a master regulator of C. albicans biofilm development, although the full extent of its regulation remains unknown. Here, we report that Bcr1 is a phosphoprotein that physically interacts with the NDR kinase Cbk1 and undergoes Cbk1-dependent phosphorylation. Mutating the two putative Cbk1 phosphoacceptor residues in Bcr1 to alanine markedly impaired Bcr1 function during biofilm formation and virulence in a mouse model of disseminated candidiasis. Cells lacking Cbk1, or any of its upstream activators, also had reduced biofilm development. Notably, mutating the two putative Cbk1 phosphoacceptor residues in Bcr1 to glutamate in cbk1Δ cells upregulated the transcription of Bcr1-dependent genes and partially rescued the biofilm defects of a cbk1Δ strain. Therefore, our data uncovered a novel role of the NDR/LATS kinase Cbk1 in the regulation of biofilm development through the control of Bcr1.

Highlights

Biofilms are surface-attached microbial communities embedded in an extracellular matrix
Genes required for hyphal morphogenesis, cell wall remodeling, amino acid and lipid metabolism and glycolytic processes have been involved in the progression of biofilm formation in C. albicans
Several genes involved in the development of biofilms of C. albicans have been identified

Summary

Introduction

Biofilms are surface-attached microbial communities embedded in an extracellular matrix. As genitourinary or oral epithelia, and biomedical devices can serve as substrates for biofilm development. In this context, biofilm formation is a key feature in microbial pathogenesis. Genes required for hyphal morphogenesis, cell wall remodeling, amino acid and lipid metabolism and glycolytic processes have been involved in the progression of biofilm formation in C. albicans (for a review, see [6]). A hypha-specific gene regulator; Bcr, required for the expression of different cell wall proteins and Zap, which governs matrix production, are examples of C. albicans biofilm transcriptional regulators [8,9,10,11]. Deletion of BCR1 results in defective biofilm formation in vivo and in vitro because of altered cell-to-cell interactions mediated by Als, Als and Hwp1 [9]

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