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Ser or Leu: structural snapshots of mistranslation in Candida albicans.

ABSTRACT: Candida albicans is a polymorphic opportunistic fungal pathogen normally residing as commensal on mucosal surfaces, skin and gastrointestinal and genitourinary tracts. However, in immunocompromised patients C. albicans can cause superficial mucosal infections or life-threatening disseminated candidemia. A change in physiological conditions triggers a cascade of molecular events leading to morphogenetic alterations and increased resistance to damage induced by host defenses. The complex biology of this human pathogen is reflected in its morphological plasticity and reinforced by the ability to ambiguously translate the universal leucine CUG codon predominantly as serine, but also as leucine. Mistranslation affects more than half of C. albicans proteome and it is widespread across many biological processes. A previous analysis of CTG-codon containing gene products in C. albicans suggested that codon ambiguity subtly shapes protein function and might have a pivotal role in signaling cascades associated with morphological changes and pathogenesis. In this review we further explore this hypothesis by highlighting the role of ambiguous decoding in macromolecular recognition of key effector proteins associated with the regulation of signal transduction cascades and the cell cycle, which are critical processes for C. albicans morphogenic plasticity under a variety of environmental conditions.

SUBMITTER: Sarkany Z

PROVIDER: S-EPMC4428446 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Ser or Leu: structural snapshots of mistranslation in Candida albicans.

Sárkány Zsuzsa Z Silva Alexandra A Pereira Pedro J B PJ Macedo-Ribeiro Sandra S

Frontiers in molecular biosciences 20141219

Candida albicans is a polymorphic opportunistic fungal pathogen normally residing as commensal on mucosal surfaces, skin and gastrointestinal and genitourinary tracts. However, in immunocompromised patients C. albicans can cause superficial mucosal infections or life-threatening disseminated candidemia. A change in physiological conditions triggers a cascade of molecular events leading to morphogenetic alterations and increased resistance to damage induced by host defenses. The complex biology o ...[more]

PMID: 25988168

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Project description:UNLABELLED:In the human fungal pathogen Candida albicans, the CUG codon is translated 97% of the time as serine and 3% of the time as leucine, which potentially originates an array of proteins resulting from the translation of a single gene. Genes encoding cell surface proteins are enriched in CUG codons; thus, CUG mistranslation may influence the interactions of the organism with the host. To investigate this, we compared a C. albicans strain that misincorporates 28% of leucine at CUGs with a wild-type parental strain. The first strain displayed increased adherence to inert and host molecules. In addition, it was less susceptible to phagocytosis by murine macrophages, probably due to reduced exposure of cell surface ?-glucans. To prove that these phenotypes occurred due to serine/leucine exchange, the C. albicans adhesin and invasin ALS3 was expressed in Saccharomyces cerevisiae in its two natural isoforms (Als3p-Leu and Als3p-Ser). The cells with heterologous expression of Als3p-Leu showed increased adherence to host substrates and flocculation. We propose that CUG mistranslation has been maintained during the evolution of C. albicans due to its potential to generate cell surface variability, which significantly alters fungus-host interactions. IMPORTANCE:The translation of genetic information into proteins is a highly accurate cellular process. In the human fungal pathogen Candida albicans, a unique mistranslation event involving the CUG codon occurs. The CUG codon is mainly translated as serine but can also be translated as leucine. Leucine and serine are two biochemically distinct amino acids, hydrophobic and hydrophilic, respectively. The increased rate of leucine incorporation at CUG decoding triggers C. albicans virulence attributes, such as morphogenesis, phenotypic switching, and adhesion. Here, we show that CUG mistranslation masks the fungal cell wall molecule ?-glucan that is normally recognized by the host immune system, delaying its response. Furthermore, we demonstrate that two different proteins of the adhesin Als3 generated by CUG mistranslation confer increased hydrophobicity and adhesion ability on yeast cells. Thus, CUG mistranslation functions as a mechanism to create protein diversity with differential activities, constituting an advantage for a mainly asexual microorganism. This could explain its preservation during evolution.

Project description:Regulated erroneous protein translation (adaptive mistranslation) increases proteome diversity and produces advantageous phenotypic variability in the human pathogen Candida albicans. It also increases fitness in the presence of fluconazole, but the underlying molecular mechanism is not understood. To address this question, we evolved hypermistranslating and wild-type strains in the absence and presence of fluconazole and compared their fluconazole tolerance and resistance trajectories during evolution. The data show that mistranslation increases tolerance and accelerates the acquisition of resistance to fluconazole. Genome sequencing, array-based comparative genome analysis, and gene expression profiling revealed that during the course of evolution in fluconazole, the range of mutational and gene deregulation differences was distinctively different and broader in the hypermistranslating strain, including multiple chromosome duplications, partial chromosome deletions, and polyploidy. Especially, the increased accumulation of loss-of-heterozygosity events, aneuploidy, translational and cell surface modifications, and differences in drug efflux seem to mediate more rapid drug resistance acquisition under mistranslation. Our observations support a pivotal role for adaptive mistranslation in the evolution of drug resistance in C. albicans. IMPORTANCE Infectious diseases caused by drug-resistant fungi are an increasing threat to public health because of the high mortality rates and high costs associated with treatment. Thus, understanding of the molecular mechanisms of drug resistance is of crucial interest for the medical community. Here we investigated the role of regulated protein mistranslation, a characteristic mechanism used by C. albicans to diversify its proteome, in the evolution of fluconazole resistance. Such codon ambiguity is usually considered highly deleterious, yet recent studies found that mistranslation can boost adaptation in stressful environments. Our data reveal that CUG ambiguity diversifies the genome in multiple ways and that the full spectrum of drug resistance mechanisms in C. albicans goes beyond the traditional pathways that either regulate drug efflux or alter the interactions of drugs with their targets. The present work opens new avenues to understand the molecular and genetic basis of microbial drug resistance.

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Ser or Leu: structural snapshots of mistranslation in Candida albicans.

Publications

Ser or Leu: structural snapshots of mistranslation in Candida albicans.

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