Reduction of histone proteins dosages increases CFW sensitivity and attenuates virulence of Candida albicans.

ABSTRACT

Histone proteins are important components of nucleosomes, which play an important role in regulating the accessibility of DNA and the function of genomes. However, the effect of histone proteins dosages on physiological processes is not clear in the human fungal pathogen Candida albicans. In this study, we found that the deletion of the histone protein H3 coding gene HHT21 and the histone protein H4 coding gene HHF1 resulted in a significant decrease in the expression dosage of the histone proteins H3 and H4, which had a significant impact on the localization of the histone protein H2A and plasmid maintenance. Stress sensitivity experiments showed that the mutants hht21Δ/Δ, hhf1Δ/Δ and hht21Δ/Δhhf1Δ/Δ were more sensitive to cell wall stress induced by Calcofluor White (CFW) than the wild-type strain. Further studies showed that the decrease in the dosage of the histone proteins H3 and H4 led to the change of cell wall components, increased chitin contents, and down-regulated expression of the SAP9, KAR2, and CRH11 genes involved in the cell wall integrity (CWI) pathway. Overexpression of SAP9 could rescue the sensitivity of the mutants to CFW. Moreover, the decrease in the histone protein s dosages affected the FAD-catalyzed oxidation of Ero1 protein, resulting in the obstruction of protein folding in the ER, and thus reduced resistance to CFW. It was also found that CFW induced a large amount of ROS accumulation in the mutants, and the addition of ROS scavengers could restore the growth of the mutants under CFW treatment. In addition, the reduction of the histone proteins dosages greatly weakened systemic infection and kidney fungal burden in mice, and hyphal development was significantly impaired in the mutants under macrophage treatment, indicating that the histone proteins dosages is very important for the virulence of C. albicans. This study revealed that histone proteins dosages play a key role in the cell wall stress response and pathogenicity in C. albicans.