The Fungus Candida albicans Tolerates Ambiguity at Multiple Codons

Abstract

The ascomycete Candida albicans is a normal resident of the gastrointestinal tract of humans and other warm-blooded animals. It occurs in a broad range of body sites and has high capacity to survive and proliferate in adverse environments with drastic changes in oxygen, carbon dioxide, pH, osmolarity, nutrients, and temperature. Its biology is unique due to flexible reassignment of the leucine CUG codon to serine and synthesis of statistical proteins. Under standard growth conditions, CUG sites incorporate leucine (3% of the times) and serine (97% of the times) on a proteome wide scale, but leucine incorporation fluctuates in response to environmental stressors and can be artificially increased up to 98%. In order to determine whether such flexibility also exists at other codons, we have constructed several serine tRNAs that decode various non-cognate codons. Expression of these tRNAs had minor effects on fitness, but growth of the mistranslating strains at different temperatures, in medium with different pH and nutrients composition was often enhanced relatively to the wild type (WT) strain, supporting our previous data on adaptive roles of CUG ambiguity in variable growth conditions. Parallel evolution of the recombinant strains (100 generations) followed by full genome resequencing identified various strain specific single nucleotide polymorphisms (SNP) and one SNP in the deneddylase (JAB1) gene in all strains. Since JAB1 is a subunit of the COP9 signalosome complex, which interacts with cullin (Cdc53p) to mediate degradation of a variety of cellular proteins, our data suggest that neddylation plays a key role in tolerance and adaptation to codon ambiguity in C. albicans.

Codon misreading tRNAs promote tumor growth in mice

“…advantageous if cells are exposed to environmental stress [31]. Since, in the present work the mutant misreading tRNAs were well tolerated and did not produce advantageous or deleterious phenotypes in vitro, we reasoned that external stimuli could be necessary to reveal putative adaptive phenotypic variation.…”

“…In addition, mixtures of these rare peptides produced by trypsin diggestion of proteomes are truly challenging to detect, even when the most sophysticated mass spectrometry instruments and software methods are used [26]. Moreover, radioactive and/or chemiluminescence methods normally used to quantify protein synthesis errors in cell cultures are not applicable to solid tumors or tissue biopsies [9,[27][28][29][30][31] complicating this issue even further. To circumvent those technical limitations, we have used highly sensitive MS/MS methods, and MS/ MS spectra searching engines that are able to identify rare peptides in proteins whose occurrence depends on the rules that govern mRNA decoding by the ribosome (knowledge based targeted searches).…”

11th IUBMB Focused Meeting on the Aminoacyl-tRNA Synthetases: Sailing a New Sea of Complex Functions in Human Biology and Disease

“…By contrast, mis-methionylation of non-cognate tRNAs may help eukaryotic cells mitigate high levels of oxidative stress [ 22 ], as does the oxidative deactivation of ThrRS editing in E. coli . In arguably the most dramatic example of the benefit of mistranslation, elevated mis-serylation of non-cognate tRNAs has been shown to enhance the pathogenicity of Saccharomyces cerevisiae and Candida albicans [ 23 ]. These observations highlight the need for improved tools to study mistranslation, including improved mass spectrometry approaches and assays for measuring quality control processes in single cells (Jiquing Ling, U. Texas).…”

Photodynamic Inactivation of Candida albicans in Blood Plasma and Whole Blood

“…Fungi inactivation seems to be less dependent on the binding of PS to cells. In the case of fungi, the free PS induces some initial changes in the plasmatic membrane and then penetrate in the cell, causing more extensive damage in more complex subcellular structures such as mitochondria or nucleus [45,47].…”

“…C. albicans is a commensal fungus that can be isolated from the gastrointestinal tract, oral and vaginal mucosa of healthy individuals, existing in balance with the bacterial flora and host immune system [49]. This fungus presents high ability to survive and proliferate in adverse environments with drastic changes in oxygen, carbon dioxide, nutrients, pH, osmolality and temperature [47]. Another important feature of C. albicans is its ability to form biofilms, that are a problem in medical practice because they can be formed in artificial heart valves and dentures, presenting resistance to various antifungal agents currently used in clinical practice, including amphotericin B and fluconazole, and have multiple mechanisms of resistance [50].…”