tRNA Modification Key for Yeast Pathogenicity

The Leidel lab and collaborators starting out from a mutation in the Ncs2 protein, found in a clinical isolate of baker's yeast, studied the function of cytoplamic tRNA 2-thiolation, for which the mutated protein is essential. The mutation found in the clinical isolate increases thiolation of tRNAs and leads to enhanced fitness of yeast carrying it. Pathogenic baker's yeast without tRNA 2-thiolation loose their pathogenicity in mice and C. albicans with reduced 2-thiolation less well infect a human cell model. Their findings showing a key role for this tRNA modification for yeast pathogenicity have been published in the article "Ncs2* mediates in vivo virulence of pathogenic yeast through sulphur modification of cytoplasmic transfer RNA " in Nucleic Acids Research.

Fungal pathogens threaten ecosystems and human health. Understanding the molecular basis of their virulence is key to develop new treatment strategies. Here, we characterize NCS2*, a point mutation identified in a clinical baker's yeast isolate. Ncs2 is essential for 2-thiolation of tRNA and the NCS2* mutation leads to increased thiolation at body temperature. NCS2* yeast exhibits enhanced fitness when grown at elevated temperatures or when exposed to oxidative stress, inhibition of nutrient signalling, and cell-wall stress. Importantly, Ncs2* alters the interaction and stability of the thiolase complex likely mediated by nucleotide binding. The absence of 2-thiolation abrogates the in vivo virulence of pathogenic baker's yeast in infected mice. Finally, hypomodification triggers changes in colony morphology and hyphae formation in the common commensal pathogen Candida albicans resulting in decreased virulence in a human cell culture model. These findings demonstrate that 2-thiolation of tRNA acts as a key mediator of fungal virulence and reveal new mechanistic insights into the function of the highly conserved tRNA-thiolase complex.

Read the Publication in Nucleic Acids Research (Open Access)

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Abstract, figure and title from Alings et al. (2023) Nucleic Acids Res published under a CC BY 4.0 license.