Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China.
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China.
Microbiol Res. 2024 Feb;279:127552. doi: 10.1016/j.micres.2023.127552. Epub 2023 Nov 19.
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.
组蛋白蛋白是核小体的重要组成部分，在调节 DNA 的可及性和基因组功能方面发挥着重要作用。然而，在人类真菌病原体白念珠菌中，组蛋白蛋白剂量对生理过程的影响尚不清楚。在这项研究中，我们发现组蛋白蛋白 H3 编码基因 HHT21 和组蛋白蛋白 H4 编码基因 HHF1 的缺失导致组蛋白蛋白 H3 和 H4 的表达剂量显著降低，这对组蛋白蛋白 H2A 的定位和质粒维持有显著影响。应激敏感实验表明，与野生型菌株相比，hht21Δ/Δ、 hhf1Δ/Δ 和 hht21Δ/Δhhf1Δ/Δ 突变体对细胞壁应激诱导的Calcofluor White (CFW)更为敏感。进一步的研究表明，组蛋白蛋白 H3 和 H4 的剂量降低导致细胞壁成分发生变化，几丁质含量增加，参与细胞壁完整性 (CWI)途径的 SAP9、KAR2 和 CRH11 基因表达下调。SAP9 的过表达可以挽救突变体对 CFW 的敏感性。此外，组蛋白蛋白 s 剂量的降低影响 FAD 催化的 Ero1 蛋白氧化，导致内质网中蛋白质折叠受阻，从而降低对 CFW 的抗性。还发现 CFW 在突变体中诱导大量 ROS 积累，添加 ROS 清除剂可以恢复 CFW 处理下突变体的生长。此外，组蛋白蛋白剂量的降低大大削弱了白念珠菌在小鼠体内的系统感染和肾脏真菌负荷，并且在巨噬细胞处理下突变体中的菌丝发育明显受损，这表明组蛋白蛋白剂量对白念珠菌的毒力非常重要。本研究揭示了组蛋白蛋白剂量在白念珠菌细胞壁应激反应和致病性中起着关键作用。
