Candida albicans CUG Mistranslation Is a Mechanism To Create Cell Surface Variation

Abstract

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 β-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.

Translation quality control is critical for bacterial responses to amino acid stress

“…In the pathogenic yeast Candida albicans an ambiguity in the genetic code results in the systematic miscoding of ∼3% of all Leu codons as Ser. This programmed miscoding event generates an array of proteins originating from a single gene that can be beneficial in some cases, for example by generating increased cell surface variation (37,38). Similar potential mistranslation benefits have been proposed in mammalian and bacterial cells in which errors in protein synthesis have been linked with increased diversity of antigen presentation (4,39,40).…”

Candida Survival Strategies

“…This in turn increases phenotypic variationdone of the most important survival skills of C. albicans (Gomes et al, 2007;Miranda et al, 2013). An important example is the variability in cell surface molecules, which is created by CUG mistranslation and which might have a major impact on the fungusehost interaction (Miranda et al, 2013). Taken together, short-and long-term reactions/adaptations to stress or other environmental conditions are regulated by chromosomal changes.…”

“…However, CUG translation is ambiguous, and partial reversion from serine to leucine identity is possible (Gomes et al, 2007), thereby leading to an exponential expansion of the C. albicans proteome. This in turn increases phenotypic variationdone of the most important survival skills of C. albicans (Gomes et al, 2007;Miranda et al, 2013). An important example is the variability in cell surface molecules, which is created by CUG mistranslation and which might have a major impact on the fungusehost interaction (Miranda et al, 2013).…”

Genetic code flexibility in microorganisms: novel mechanisms and impact on physiology

“…Altering the ratio of Ser to Leu incorporation at CUG codons introduces diverse cell and colony morphologies, as well as distinct antifungal and immune responses 50,51 . Wild-type C. albicans encodes a CUG-decoding tRNA CAG that is recognized by both SerRS and LeuRS (FIG.…”

“…4). Enhanced CUG ambiguity increases cell adhesion by ambiguous translation of adhesins and reduces susceptibility to macrophage killing by decreasing surface exposure of β-glucans 51 . It has also been shown that, in Mycobacterium smegmatis , the level of ambiguous decoding at Asn codons increases during stationary phase and under low pH conditions 52 .…”