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Integration of Posttranscriptional Gene Networks into Metabolic Adaptation and Biofilm Maturation in Candida albicans.

Verma-Gaur J, Qu Y, Harrison PF, Lo TL, Quenault T, Dagley MJ, Bellousoff M, Powell DR, Beilharz TH, Traven A - PLoS Genet. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Infection and Immunity Program, Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

Biofilm mRNA targets of the Pumilio RNA binding protein Puf3.(A) Analysis of the gene expression data from [14] revealed that 162 genes down-regulated in biofilms are annotated to GO “Mitochondrion”, and 36/162 contain a Puf3 recognition element in their 3’ UTR. The putative biofilm-regulated Puf3 targets include several important mitochondrial biogenesis factors, such as mitochondrial ribosomal subunits, proteins required for respiratory chain function and assembly, and proteins that belong to the mitochondrial protein import machinery. Gene Ontology analysis was performed using the tools in the Candida Genome Database. (B) Cartoon of the Puf3 RNA binding domain from S. cerevisiae showing binding to the core recognition element and the interaction with the -2 cytosine (based on the structure reported in [39]. (C) Alignment of the PUM domains of the C. albicans and S. cerevisiae Puf3 proteins containing the 8–8’ repeat. The LAS motif of the Puf3 binding pocket that interacts with the -2 cytosine is boxed in blue, and this binding pocket is conserved in the C. albicans protein (see also [66]).
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pgen.1005590.g001: Biofilm mRNA targets of the Pumilio RNA binding protein Puf3.(A) Analysis of the gene expression data from [14] revealed that 162 genes down-regulated in biofilms are annotated to GO “Mitochondrion”, and 36/162 contain a Puf3 recognition element in their 3’ UTR. The putative biofilm-regulated Puf3 targets include several important mitochondrial biogenesis factors, such as mitochondrial ribosomal subunits, proteins required for respiratory chain function and assembly, and proteins that belong to the mitochondrial protein import machinery. Gene Ontology analysis was performed using the tools in the Candida Genome Database. (B) Cartoon of the Puf3 RNA binding domain from S. cerevisiae showing binding to the core recognition element and the interaction with the -2 cytosine (based on the structure reported in [39]. (C) Alignment of the PUM domains of the C. albicans and S. cerevisiae Puf3 proteins containing the 8–8’ repeat. The LAS motif of the Puf3 binding pocket that interacts with the -2 cytosine is boxed in blue, and this binding pocket is conserved in the C. albicans protein (see also [66]).

Mentions: Inspection of the Nobile et al data [14] revealed that of the 622 genes down-regulated in biofilms relative to growth in suspension, 162 are annotated to the GO term “Mitochondrion” (p = 1.40E-10, FDR≈0) (S1 Dataset and Fig 1A). Of these, based on inferred functions from homology to the model yeast S. cerevisiae, we judged that 29 genes are likely to have dominant functions in other organelles (S1 Dataset). For example, some of the genes encode glycolytic enzymes, enzymes of ergosterol biosynthesis in the endoplasmic reticulum, cytoplasmic ribosome subunits and translation factors, and proteins with nuclear roles (S1 Dataset). In several cases, their annotation to mitochondria is based on proteomics studies that found the proteins in the mitochondrial proteome [32,33]. However, caution has to be applied, particularly when abundant proteins, as well as structures associated with mitochondria, such as the endoplasmic reticulum and mitochondria-associated translation, are considered. Whether these proteins play a role in mitochondrial activity/biogenesis in C. albicans remains to be studied.


Integration of Posttranscriptional Gene Networks into Metabolic Adaptation and Biofilm Maturation in Candida albicans.

Verma-Gaur J, Qu Y, Harrison PF, Lo TL, Quenault T, Dagley MJ, Bellousoff M, Powell DR, Beilharz TH, Traven A - PLoS Genet. (2015)

Biofilm mRNA targets of the Pumilio RNA binding protein Puf3.(A) Analysis of the gene expression data from [14] revealed that 162 genes down-regulated in biofilms are annotated to GO “Mitochondrion”, and 36/162 contain a Puf3 recognition element in their 3’ UTR. The putative biofilm-regulated Puf3 targets include several important mitochondrial biogenesis factors, such as mitochondrial ribosomal subunits, proteins required for respiratory chain function and assembly, and proteins that belong to the mitochondrial protein import machinery. Gene Ontology analysis was performed using the tools in the Candida Genome Database. (B) Cartoon of the Puf3 RNA binding domain from S. cerevisiae showing binding to the core recognition element and the interaction with the -2 cytosine (based on the structure reported in [39]. (C) Alignment of the PUM domains of the C. albicans and S. cerevisiae Puf3 proteins containing the 8–8’ repeat. The LAS motif of the Puf3 binding pocket that interacts with the -2 cytosine is boxed in blue, and this binding pocket is conserved in the C. albicans protein (see also [66]).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608769&req=5

pgen.1005590.g001: Biofilm mRNA targets of the Pumilio RNA binding protein Puf3.(A) Analysis of the gene expression data from [14] revealed that 162 genes down-regulated in biofilms are annotated to GO “Mitochondrion”, and 36/162 contain a Puf3 recognition element in their 3’ UTR. The putative biofilm-regulated Puf3 targets include several important mitochondrial biogenesis factors, such as mitochondrial ribosomal subunits, proteins required for respiratory chain function and assembly, and proteins that belong to the mitochondrial protein import machinery. Gene Ontology analysis was performed using the tools in the Candida Genome Database. (B) Cartoon of the Puf3 RNA binding domain from S. cerevisiae showing binding to the core recognition element and the interaction with the -2 cytosine (based on the structure reported in [39]. (C) Alignment of the PUM domains of the C. albicans and S. cerevisiae Puf3 proteins containing the 8–8’ repeat. The LAS motif of the Puf3 binding pocket that interacts with the -2 cytosine is boxed in blue, and this binding pocket is conserved in the C. albicans protein (see also [66]).
Mentions: Inspection of the Nobile et al data [14] revealed that of the 622 genes down-regulated in biofilms relative to growth in suspension, 162 are annotated to the GO term “Mitochondrion” (p = 1.40E-10, FDR≈0) (S1 Dataset and Fig 1A). Of these, based on inferred functions from homology to the model yeast S. cerevisiae, we judged that 29 genes are likely to have dominant functions in other organelles (S1 Dataset). For example, some of the genes encode glycolytic enzymes, enzymes of ergosterol biosynthesis in the endoplasmic reticulum, cytoplasmic ribosome subunits and translation factors, and proteins with nuclear roles (S1 Dataset). In several cases, their annotation to mitochondria is based on proteomics studies that found the proteins in the mitochondrial proteome [32,33]. However, caution has to be applied, particularly when abundant proteins, as well as structures associated with mitochondria, such as the endoplasmic reticulum and mitochondria-associated translation, are considered. Whether these proteins play a role in mitochondrial activity/biogenesis in C. albicans remains to be studied.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Infection and Immunity Program, Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.

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.

No MeSH data available.


Related in: MedlinePlus