Fungal acetylome comparative analysis identifies an essential role of acetylation in human fungal pathogen virulence

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.

Lysine acetylation contributes to development, aflatoxin biosynthesis and pathogenicity in Aspergillus flavus

“…And orthologs of these acetylated proteins have been shown to be involved in virulence in pathogenic fungi, including F. graminearum (Zheng et al ., ; Liu et al ., ), C. albicans (Gong et al ., ) and B. cinerea (Gonzalez et al ., ), indicating that acetylation may contribute to pathogenicity in A. flavus . In addition, the latest research also showed that in human fungal pathogens, such as Cryptococcus neoformans , C. albicans , and A. fumigatus , the levels of protein acetylation in pathogenic fungi correlate with their pathogenicity (Li et al ., ).Our results also proved that acetylation modification of AflO at K241 and K384 plays critical roles in the pathogenicity of A. flavus . One contributing factor to this defect in pathogenicity is that conidiation dramatically decreased in the Δ aflO and K241R site mutants when compared with WT, and development is thought to be one of the main factors in pathogenicity of A. flavus (Amaike and Keller, ).…”

Post-Translational Modifications Drive Success and Failure of Fungal–Host Interactions

“…A complementary study featuring an acetylome comparative analysis revealed an interspecies contrast between nonpathogenic S. cerevisiae to highly virulent C. neoformans, A. fumigatus, and C. albicans. Essential roles for acetylation in these fungal pathogens were identified and determined that protein acetylation levels correlate to fungal pathogenicity [76]. Here, the authors identified 159 genes co-regulated by KDACs, Dac2 and Dac4, key regulators of fungal virulence, and revealed highly dynamic features of acetylation within fungal species.…”

Exploring the Histone Acetylation Cycle in the Protozoan Model Tetrahymena thermophila

“…Histone acetylation occurs either at the nucleosomal level by type A HATs [SAGA (Baker and Grant, 2007) and NuA4 (Doyon and Cote, 2004) complexes] or on histones prior to their deposition into chromatin by type B HATs [Hat1 (Parthun, 2007), Rtt109 (Fillingham et al, 2008)]. Although the focus of this review is histone acetylation, it is important to note that proteomic studies have identified hundreds to thousands of acetylated proteins in a variety of model systems from parasitic protozoa to mammalian cells (Zhao et al, 2010;Jeffers and Sullivan, 2012;Miao et al, 2013;Li et al, 2019). To reflect this, HATs and HDACs that acetylate/deacetylate the group of lysine residues on non-histone substrates are also be referred to as lysine acetyltransferases/deacetylases (KATs/KDACs) (Allis et al, 2007).…”