Histone Acetylation Regulator Gcn5 Mediates Drug Resistance and Virulence of Candida glabrata.
Histone Acetylation Regulator Gcn5 Mediates Drug Resistance and Virulence of Candida glabrata.
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DOI：
10.1128/spectrum.00963-22
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发表时间：
2022-06-29
影响因子：
3.7
通讯作者：
Zhao, Yanan
中科院分区：
文献类型：
--
作者：
Yu, Shuying;Paderu, Padmaja;Lee, Annie;Eirekat, Sami;Healey, Kelley;Chen, Liang;Perlin, David S.;Zhao, Yanan
光滑念珠菌准备迅速适应药物压力，并获得抗真菌药物耐药性，导致治疗失败。鉴于有限的抗真菌药物，探索抗真菌治疗的新靶点或治疗策略的需求尚未得到满足。赖氨酸乙酰转移酶Gcn 5与C.白色念珠菌。然而，Gcn 5是如何发挥作用并影响C. glabrata未知。破坏GCN 5使C. glabrata细胞对各种应激源更敏感，部分逆转了耐药突变体的耐药性，并与野生型细胞相比减弱了耐药性的出现。RNA测序（RNA-seq）分析显示，与野生型细胞相比，gcn 5 Δ细胞中涉及多个生物学过程和对抗真菌药物的不同转录应答的转录组学变化。GCN 5缺失也导致THP-1巨噬细胞内细胞内存活减少。总之，Gcn 5在调节C. glabrata和调节其对抗真菌压力和宿主防御的反应。重要性作为一种重要且成功的人类病原体，光滑念珠菌以其快速适应和快速获得对最常用的抗真菌药物的耐药性而闻名，导致临床治疗失败。在这里，我们描述了组蛋白乙酰转移酶Gcn 5是适应抗真菌压力和发展耐药性的关键因素。光滑的这些结果为C. glabrata，并可能是有用的药物靶点发现和新的治疗策略，以打击真菌感染的发展。
Candida glabrata is poised to adapt to drug pressure rapidly and acquire antifungal resistance leading to therapeutic failure. Given the limited antifungal armamentarium, there is an unmet need to explore new targets or therapeutic strategies for antifungal treatment. The lysine acetyltransferase Gcn5 has been implicated in the pathogenesis of C. albicans. Yet how Gcn5 functions and impacts antifungal resistance in C. glabrata is unknown. Disrupting GCN5 rendered C. glabrata cells more sensitive to various stressors, partially reverted resistance in drug-resistant mutants, and attenuated the emergence of resistance compared to wild-type cells. RNA sequencing (RNA-seq) analysis revealed transcriptomic changes involving multiple biological processes and different transcriptional responses to antifungal drugs in gcn5Δ cells compared to wild-type cells. GCN5 deletion also resulted in reduced intracellular survival within THP-1 macrophages. In summary, Gcn5 plays a critical role in modulating the virulence of C. glabrata and regulating its response to antifungal pressure and host defense. IMPORTANCE As an important and successful human pathogen, Candida glabrata is known for its swift adaptation and rapid acquisition of resistance to the most commonly used antifungal agents, resulting in therapeutic failure in clinical settings. Here, we describe that the histone acetyltransferase Gcn5 is a key factor in adapting to antifungal pressure and developing resistance in C. glabrata. The results provide new insights into epigenetic control over the drug response in C. glabrata and may be useful for drug target discovery and the development of new therapeutic strategies to combat fungal infections.
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影响因子：
--
作者：
Li QQ;Skinner J;Bennett JE
通讯作者：
Bennett JE
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
56.9
作者：
Domergue, R;Castaño, I;Cormack, BP
通讯作者：
Cormack, BP
影响因子：
6.7
作者：
Kuchler K;Jenull S;Shivarathri R;Chauhan N
通讯作者：
Chauhan N
影响因子：
6.4
作者：
Garcia-Rubio R;Jimenez-Ortigosa C;DeGregorio L;Quinteros C;Shor E;Perlin DS
通讯作者：
Perlin DS