Lin Chi-Jan, Yang Sheng-Yung, Hsu Li-Hang, Yu Shang-Jie, Chen Ying-Lien
Institute of Molecular Biology, National Chung Hsing University, 40227 Taichung, Taiwan.
Department of Plant Pathology and Microbiology, National Taiwan University, 10617 Taipei, Taiwan.
Med Mycol. 2023 Feb 3;61(2). doi: 10.1093/mmy/myad004.
Candida glabrata is an opportunistic fungal pathogen and the second most prevalent species isolated from candidiasis patients. C. glabrata has intrinsic tolerance to antifungal drugs and oxidative stresses and the ability to adhere to mucocutaneous surfaces. However, knowledge about the regulation of its virulence traits is limited. The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex modulates gene transcription by histone acetylation through the histone acetyltransferase (HAT) module comprised of Gcn5-Ada2-Ada3. Previously, we showed that the ada2 mutant was hypervirulent but displayed decreased tolerance to antifungal drugs and cell wall perturbing agents. In this study, we further characterized the functions of Ada3 and Gcn5 in C. glabrata. We found that single, double, or triple deletions of the HAT module, as expected, resulted in a decreased level of acetylation on histone H3 lysine 9 (H3K9) and defective growth. These mutants were more susceptible to antifungal drugs, oxidative stresses, and cell wall perturbing agents compared with the wild-type. In addition, HAT module mutants exhibited enhanced agar invasion and upregulation of adhesin and proteases encoding genes, whereas the biofilm formation of those mutants was impaired. Interestingly, HAT module mutants exhibited enhanced induction of catalases (CTA1) expression upon treatment with H2O2 compared with the wild-type. Lastly, although ada3 and gcn5 exhibited marginal hypervirulence, the HAT double and triple mutants were hypervirulent in a murine model of candidiasis. In conclusion, the HAT module of the SAGA complex plays unique roles in H3K9 acetylation, drug tolerance, oxidative stress response, adherence, and virulence in C. glabrata.
光滑念珠菌是一种机会性真菌病原体，是从念珠菌病患者中分离出的第二常见菌种。光滑念珠菌对抗真菌药物和氧化应激具有内在耐受性，并且能够粘附于粘膜皮肤表面。然而，关于其毒力特性调控的知识有限。Spt-Ada-Gcn5 乙酰转移酶（SAGA）复合物通过由 Gcn5-Ada2-Ada3 组成的组蛋白乙酰转移酶（HAT）模块进行组蛋白乙酰化来调节基因转录。此前，我们发现 ada2 突变体具有高毒力，但对抗真菌药物和细胞壁干扰剂的耐受性降低。在本研究中，我们进一步表征了 Ada3 和 Gcn5 在光滑念珠菌中的功能。我们发现，正如预期的那样，HAT 模块的单缺失、双缺失或三缺失导致组蛋白 H3 赖氨酸 9（H3K9）上的乙酰化水平降低以及生长缺陷。与野生型相比，这些突变体对抗真菌药物、氧化应激和细胞壁干扰剂更敏感。此外，HAT 模块突变体表现出增强的琼脂侵袭能力以及粘附素和蛋白酶编码基因的上调，而这些突变体的生物膜形成受损。有趣的是，与野生型相比，HAT 模块突变体在用 H2O2 处理后过氧化氢酶（CTA1）表达的诱导增强。最后，尽管 ada3 和 gcn5 表现出轻微的高毒力，但 HAT 双突变体和三突变体在念珠菌病小鼠模型中具有高毒力。总之，SAGA 复合物的 HAT 模块在光滑念珠菌的 H3K9 乙酰化、药物耐受性、氧化应激反应、粘附和毒力中发挥独特作用。
