Candida albicans is a polymorphic yeast that can cause life threatening systemic infections in immuno-compromised individuals. One key attribute of C. albicans that enhances its pathogenicity is the ability to switch morphologies between filamentous and vegetative modes in response to specific environmental conditions. Stressful changes in such cellular conditions commonly cause a rapid inhibition of global protein synthesis leading to altered programmes of gene expression. In Saccharomyces cerevisiae, fusel alcohols signal nitrogen scarcity and induce pseudohyphal growth enabling yeast colonies to spread towards nutrient replete areas. These alcohols also inhibit protein synthesis by targeting the translation initiation factor, eIF2B. eIF2B is the guanine nucleotide exchange factor for eIF2, which supports eIF2-GTP production and represents a key regulated step in translation initiation. eIF2-GTP interacts with Met-tRNAiMet to form the ternary complex which is essential for translation initiation. Fusel alcohols target eIF2B leading to reduced levels of ternary complex and reduced protein synthesis. In Candida albicans, a variety of cell biological and genetic assays suggest that fusel alcohols and ethanol inhibit protein synthesis by targeting the translation initiation factor, eIF2B, and they also induce hyphal/pseudohyphal growth, a process that is associated with pathogenesis in C. albicans. In contrast to fusel alcohols, farnesol, aquorum sensing alcohol, does not appear to impact upon eIF2B activity. Rather, biochemical and mass spectrometric analysis suggest farnesol affects the interaction of the mRNA with the small ribosomal subunit during translation initiation. Further elucidation of the effect of farnesol on C. albicans transcript levels and ribosome association by next generation sequencing gave insight into the genes that are differentially expressed following farnesol treatment. While genes involved inmorphological differentiation were generally repressed, those involved in protein synthesis were upregulated, possibly as an adaptive response to inhibition of protein synthesis by farnesol. Intriguingly, the regulation of these functional categories of genes occurred in a co-ordinated manner at either the transcript level or at the level of ribosome association, but rarely was gene expression regulated at both transcriptional and post-transcriptional levels for the same gene.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:686751 |
| Date | January 2015 |
| Creators | Egbe, Nkechi |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/translational-and-morphological-effects-of-signalling-alcohols-on-c-albicans(3de9928c-bf7d-4fa6-9772-2310db654e16).html |
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