title: Integration of Posttranscriptional Gene Networks into Metabolic Adaptation and Biofilm Maturation in Candida albicans.
abstract: The yeast Candida albicans is a human commensal and opportunistic pathogen. Although both commensalism and pathogenesis depend on metabolic adaptation, the regulatory pathways that mediate metabolic processes in C. albicans are incompletely defined. For example, metabolic change is a major feature that distinguishes community growth of C. albicans in biofilms compared to suspension cultures, but how metabolic adaptation is functionally interfaced with the structural and gene regulatory changes that drive biofilm maturation remains to be fully understood. We show here that the RNA binding protein Puf3 regulates a posttranscriptional mRNA network in C. albicans that impacts on mitochondrial biogenesis, and provide the first functional data suggesting evolutionary rewiring of posttranscriptional gene regulation between the model yeast Saccharomyces cerevisiae and C. albicans. A proportion of the Puf3 mRNA network is differentially expressed in biofilms, and by using a mutant in the mRNA deadenylase CCR4 (the enzyme recruited to mRNAs by Puf3 to control transcript stability) we show that posttranscriptional regulation is important for mitochondrial regulation in biofilms. Inactivation of CCR4 or dis-regulation of mitochondrial activity led to altered biofilm structure and over-production of extracellular matrix material. The extracellular matrix is critical for antifungal resistance and immune evasion, and yet of all biofilm maturation pathways extracellular matrix biogenesis is the least understood. We propose a model in which the hypoxic biofilm environment is sensed by regulators such as Ccr4 to orchestrate metabolic adaptation, as well as the regulation of extracellular matrix production by impacting on the expression of matrix-related cell wall genes. Therefore metabolic changes in biofilms might be intimately linked to a key biofilm maturation mechanism that ultimately results in untreatable fungal disease.
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Jiyoti
authors.initials: J
authors.lastname: Verma-Gaur
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; Infection and Immunity Program, Biomedicine Discovery Institute and the Department of Microbiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Monash Bioinformatics Platform, Monash University, Clayton, Victoria, Australia.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Harrison
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Tricia L
authors.initials: TL
authors.lastname: Lo
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Tara
authors.initials: T
authors.lastname: Quenault
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dagley
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute and the Department of Microbiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bellousoff
authors.affiliation: Monash Bioinformatics Platform, Monash University, Clayton, Victoria, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.affiliation: Development and Stem Cells Program, Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Traude H
authors.initials: TH
authors.lastname: Beilharz
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Ana
authors.initials: A
authors.lastname: Traven
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D018441:Biofilms / Q000254:growth & development*; D002176:Candida albicans / Q000235:genetics* / Q000254:growth & development; D005656:Fungal Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D012260:Ribonucleases / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D005656:Fungal Proteins; C510155:PUF3 protein, S cerevisiae; D016601:RNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; C078657:CCR4 protein, S cerevisiae; D012260:Ribonucleases