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敲除白念珠菌 TLO 基因家族导致膜甾醇组成和氟康唑耐受性改变。

Deletion of the Candida albicans TLO gene family results in alterations in membrane sterol composition and fluconazole tolerance.

机构信息

Division of Oral Biosciences, Dublin Dental University Hospital, and School of Dental Science, Trinity College Dublin, Dublin, Ireland.

Institute of Life Science, Singleton Campus, Swansea University, Swansea, Wales, United Kingdom.

出版信息

PLoS One. 2024 Aug 9;19(8):e0308665. doi: 10.1371/journal.pone.0308665. eCollection 2024.

DOI:10.1371/journal.pone.0308665
PMID:39121069
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11315338/
Abstract

Development of resistance and tolerance to antifungal drugs in Candida albicans can compromise treatment of infections caused by this pathogenic yeast species. The uniquely expanded C. albicans TLO gene family is comprised of 14 paralogous genes which encode Med2, a subunit of the multiprotein Mediator complex which is involved in the global control of transcription. This study investigates the acquisition of fluconazole tolerance in a mutant in which the entire TLO gene family has been deleted. This phenotype was reversed to varying degrees upon reintroduction of representative members of the alpha- and beta-TLO clades (i.e. TLO1 and TLO2), but not by TLO11, a gamma-clade representative. Comparative RNA sequencing analysis revealed changes in the expression of genes involved in a range of cellular functions, including ergosterol biosynthesis, mitochondrial function, and redox homeostasis. This was supported by the results of mass spectrometry analysis, which revealed alterations in sterol composition of the mutant cell membrane. Our data suggest that members of the C. albicans TLO gene family are involved in the control of ergosterol biosynthesis and mitochondrial function and may play a role in the responses of C. albicans to azole antifungal agents.

摘要

白色念珠菌对抗真菌药物的耐药性和耐受性的发展可能会影响对这种致病性酵母物种引起的感染的治疗。独特扩展的白色念珠菌 TLO 基因家族由 14 个基因组成，这些基因编码 Med2，这是多蛋白 Mediator 复合物的一个亚基，该复合物参与转录的全局控制。本研究调查了在整个 TLO 基因家族缺失的突变体中获得氟康唑耐受性的情况。在重新引入代表 alpha 和 beta-TLO 分支（即 TLO1 和 TLO2）的成员时，这种表型在不同程度上得到了逆转，但代表 gamma 分支的 TLO11 则没有。比较 RNA 测序分析显示，参与一系列细胞功能的基因的表达发生了变化，包括麦角固醇生物合成、线粒体功能和氧化还原稳态。这一结果得到了质谱分析结果的支持，该结果显示突变体细胞膜中固醇组成的改变。我们的数据表明，白色念珠菌 TLO 基因家族的成员参与了麦角固醇生物合成和线粒体功能的控制，并可能在白色念珠菌对唑类抗真菌药物的反应中发挥作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/f2479ddb7feb/pone.0308665.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/d00a924566e8/pone.0308665.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/3502d92c1e9c/pone.0308665.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/ef1c542db693/pone.0308665.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/1185445b1f8d/pone.0308665.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/02d1c64d8de7/pone.0308665.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/f8327f1c7d34/pone.0308665.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/f2479ddb7feb/pone.0308665.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/d00a924566e8/pone.0308665.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/3502d92c1e9c/pone.0308665.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/ef1c542db693/pone.0308665.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/1185445b1f8d/pone.0308665.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/02d1c64d8de7/pone.0308665.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/f8327f1c7d34/pone.0308665.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6205/11315338/f2479ddb7feb/pone.0308665.g007.jpg

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