Abstract
Lysine acetylation is critical in regulating important biological processes in many organisms, yet little is known about acetylome evolution and its contribution to phenotypic diversity. Here, we compare the acetylomes of baker’s yeast and the three deadliest human fungal pathogens, Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus. Using mass spectrometry enriched for acetylated peptides together with public data from Saccharomyces cerevisiae, we show that fungal acetylomes are characterized by dramatic evolutionary dynamics and limited conservation in core biological processes. Notably, the levels of protein acetylation in pathogenic fungi correlate with their pathogenicity. Using gene knockouts and pathogenicity assays in mice, we identify deacetylases with critical roles in virulence and protein translation elongation. Finally, through mutational analysis of deactylation motifs we find evidence of positive selection at specific acetylation motifs in fungal pathogens. These results shed new light on the pathogenicity regulation mechanisms underlying the evolution of fungal acetylomes.
Highlights
Lysine acetylation is critical in regulating important biological processes in many organisms, yet little is known about acetylome evolution and its contribution to phenotypic diversity
The Kac modifications of the orthologs that are involved in core biological processes, including protein translation, histone modifications, tricarboxylic acid (TCA) cycle, and respiration are conserved across species, the Kac sites are only partially conserved
Despite the highly dynamic occurrence of fungal acetylation sites, C. neoformans, C. albicans, and A. fumigatus reveal that the acetylomes of pathogenic fungi share commonly conserved Kac motifs that are different from those in S. cerevisiae
Summary
Lysine acetylation is critical in regulating important biological processes in many organisms, yet little is known about acetylome evolution and its contribution to phenotypic diversity. C. albicans is recognized as a commensal fungus in a majority of the human population, but it can become a causative agent of bloodstream, skin, oral and gastrointestinal infections[13,14] These fungal species span a dramatic and wide evolutionary range and demonstrate distinct phenotypic differences such as cell morphological changes, pathogenicity, and cell biology, and they can provide valuable tools for analyzing acetylome evolutionary mechanisms. What is the major effect of deacetylase inhibitors as anti-fungal agents, and do they work through inhibition of virulence producing machinery or certain core biological fungal processes, and most importantly, do the inhibitory effects block conserved acetylated processes in the host cells?. Despite the highly dynamic occurrence of fungal acetylation sites, C. neoformans, C. albicans, and A. fumigatus reveal that the acetylomes of pathogenic fungi share commonly conserved Kac motifs that are different from those in S. cerevisiae. Mutating pathogen-specific Kac motifs in C. neoformans result in the attenuation of the fitness of the mutants in the host
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