Limits...
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

Model for the role of posttranscriptional gene regulation and mitochondrial activity in biofilm matrix production and stress protection.As the biofilms mature, environmental changes, such as hypoxia and nutrients, lead to lowering of mitochondrial activity. Lower mitochondrial activity might be sensed as a stress signal and drive the production of protective extracellular matrix. Cell wall integrity pathways are known to function in matrix production [15,16], and mitochondrial function has been linked to pathways of fungal cell wall integrity (reviewed in [27]), thus providing a plausible mechanism of mitochondrial control over biofilm matrix production. Mitochondrial dysfunction could also lead to weaker cell walls and cell lysis, further contributing to extracellular matrix deposition. Posttranscriptional regulators, such as the Ccr4-NOT mRNA deadenylase and Puf3, coordinate biofilm maturation pathways by responding to nutrients and hypoxia to adjust mitochondrial biogenesis, as well as the expression of genes needed for biofilm matrix production.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4608769&req=5

pgen.1005590.g009: Model for the role of posttranscriptional gene regulation and mitochondrial activity in biofilm matrix production and stress protection.As the biofilms mature, environmental changes, such as hypoxia and nutrients, lead to lowering of mitochondrial activity. Lower mitochondrial activity might be sensed as a stress signal and drive the production of protective extracellular matrix. Cell wall integrity pathways are known to function in matrix production [15,16], and mitochondrial function has been linked to pathways of fungal cell wall integrity (reviewed in [27]), thus providing a plausible mechanism of mitochondrial control over biofilm matrix production. Mitochondrial dysfunction could also lead to weaker cell walls and cell lysis, further contributing to extracellular matrix deposition. Posttranscriptional regulators, such as the Ccr4-NOT mRNA deadenylase and Puf3, coordinate biofilm maturation pathways by responding to nutrients and hypoxia to adjust mitochondrial biogenesis, as well as the expression of genes needed for biofilm matrix production.

Mentions: Based on the data presented here, we propose a model in which metabolic and mitochondrial reprogramming in biofilms drive the pathways of biofilm maturation (Fig 9). In this model, changes to mitochondrial activity and biogenesis in the biofilm environment, possibly due to hypoxia, constitute the signal that triggers activation of protective mechanisms. This ultimately leads to extracellular matrix accumulation, potentially through the cross-talk between mitochondrial function and the pathways of cell wall biogenesis and overall cell stability (reviewed in [27]). Ccr4 is involved in the response to hypoxia, and it orchestrates biofilm maturation by adjusting the expression of cell wall genes with roles in matrix production, as well as by regulating mitochondrial biogenesis and activity. In conclusion, we suggest that the interface between metabolic and developmental restructuring in biofilms has important consequences for matrix production, a phenotype that is implicated in both antifungal and immune resistance of the biofilm growth mode. This should be considered in the context of antifungal strategies that target metabolic regulators.


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)

Model for the role of posttranscriptional gene regulation and mitochondrial activity in biofilm matrix production and stress protection.As the biofilms mature, environmental changes, such as hypoxia and nutrients, lead to lowering of mitochondrial activity. Lower mitochondrial activity might be sensed as a stress signal and drive the production of protective extracellular matrix. Cell wall integrity pathways are known to function in matrix production [15,16], and mitochondrial function has been linked to pathways of fungal cell wall integrity (reviewed in [27]), thus providing a plausible mechanism of mitochondrial control over biofilm matrix production. Mitochondrial dysfunction could also lead to weaker cell walls and cell lysis, further contributing to extracellular matrix deposition. Posttranscriptional regulators, such as the Ccr4-NOT mRNA deadenylase and Puf3, coordinate biofilm maturation pathways by responding to nutrients and hypoxia to adjust mitochondrial biogenesis, as well as the expression of genes needed for biofilm matrix production.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005590.g009: Model for the role of posttranscriptional gene regulation and mitochondrial activity in biofilm matrix production and stress protection.As the biofilms mature, environmental changes, such as hypoxia and nutrients, lead to lowering of mitochondrial activity. Lower mitochondrial activity might be sensed as a stress signal and drive the production of protective extracellular matrix. Cell wall integrity pathways are known to function in matrix production [15,16], and mitochondrial function has been linked to pathways of fungal cell wall integrity (reviewed in [27]), thus providing a plausible mechanism of mitochondrial control over biofilm matrix production. Mitochondrial dysfunction could also lead to weaker cell walls and cell lysis, further contributing to extracellular matrix deposition. Posttranscriptional regulators, such as the Ccr4-NOT mRNA deadenylase and Puf3, coordinate biofilm maturation pathways by responding to nutrients and hypoxia to adjust mitochondrial biogenesis, as well as the expression of genes needed for biofilm matrix production.
Mentions: Based on the data presented here, we propose a model in which metabolic and mitochondrial reprogramming in biofilms drive the pathways of biofilm maturation (Fig 9). In this model, changes to mitochondrial activity and biogenesis in the biofilm environment, possibly due to hypoxia, constitute the signal that triggers activation of protective mechanisms. This ultimately leads to extracellular matrix accumulation, potentially through the cross-talk between mitochondrial function and the pathways of cell wall biogenesis and overall cell stability (reviewed in [27]). Ccr4 is involved in the response to hypoxia, and it orchestrates biofilm maturation by adjusting the expression of cell wall genes with roles in matrix production, as well as by regulating mitochondrial biogenesis and activity. In conclusion, we suggest that the interface between metabolic and developmental restructuring in biofilms has important consequences for matrix production, a phenotype that is implicated in both antifungal and immune resistance of the biofilm growth mode. This should be considered in the context of antifungal strategies that target metabolic regulators.

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