Amplification of TLO Mediator Subunit Genes Facilitate Filamentous Growth in Candida Spp.
Amplification of TLO Mediator Subunit Genes Facilitate Filamentous Growth in Candida Spp.
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DOI：
10.1371/journal.pgen.1006373
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发表时间：
2016-10
期刊：
影响因子：
4.5
通讯作者：
Myers LC
中科院分区：
文献类型：
--
作者：
Liu Z;Moran GP;Sullivan DJ;MacCallum DM;Myers LC
丝状生长是C.白色念珠菌的致病性相比，毒性较低的子囊菌。许多转录因子响应于特定的环境信号调节丝状体的生长。然而，我们的工作表明了C。导致其丝状生长可塑性的白念珠菌可能与一般转录机制的变化有关，而不是转录因子及其特定靶点。C.白色念珠菌及其毒性较低的亲戚，包括其最近的亲戚C。dubliniensis的TLO基因家族是C.白色念珠菌。单个Tlo蛋白是介体（Mediator）的真菌特异性亚基，介体是一种大的多亚基真核转录共激活因子复合物。这种扩增导致在C中存在大量的“游离的"非介体相关的Tlo蛋白。albicans，而C. dubliniensis或其它毒力减弱的子囊菌。我们表明，工程一个大的'自由'池的C。dubliniensis Tlo 2（CdTlo 2）蛋白在C. dubliniensis通过过表达，导致了许多通常仅与C.白色念珠菌这些表型的幅度与过表达的CdTlo2蛋白的量成比例。其他C. dubliniensis和C.白色念珠菌Tlo蛋白确实导致这些表型。Tlo蛋白及其直系同源物含有介体相互作用结构域和有效的转录激活结构域。由Tlo介体结合结构域天然促进或通过附加的核定位信号人工促进的CdTlo 2激活结构域的核定位对于CdTlo 2过表达表型是足够的。梭白色念珠菌med3无效突变体导致多种缺陷，包括不能将Tlo蛋白定位于细胞核和在鼠全身感染模型中降低的毒力。我们的数据支持了一个模型，其中“游离”Tlo蛋白的激活结构域与DNA结合的转录因子竞争调节C.白念珠菌细胞生理学在美国，子囊菌真菌白色念珠菌是医院获得性血流感染的主要原因。由于抗真菌药物选择有限，每年约有40%的死亡率和超过10，000例与系统性C相关的死亡。白色念珠菌感染不知道为什么C。与相关的子囊菌如都柏林念珠菌相比，白色念珠菌是系统性念珠菌病的主要原因。C.白色念珠菌和C. dubliniensis之间非常相似，而C. Dubliniensis具有降低的毒力并且表现出更小的表型可塑性。真菌之间的一个显著的基因组差异是C.白念珠菌，其编码介体共激活因子复合物的真菌特异性亚基。扩增导致在C. albicans，在C.都柏林的。在C中工程化Tlo蛋白的大的“游离”池。dubliniensis通过过量表达，导致C. albicans，但在C.都柏林的。Tlo蛋白含有有效的转录激活结构域。TLO激活结构域的核定位对于TLO过表达表型是必要且充分的。本研究为C.白念珠菌可增强其毒力。
Filamentous growth is a hallmark of C. albicans pathogenicity compared to less-virulent ascomycetes. A multitude of transcription factors regulate filamentous growth in response to specific environmental cues. Our work, however, suggests the evolutionary history of C. albicans that resulted in its filamentous growth plasticity may be tied to a change in the general transcription machinery rather than transcription factors and their specific targets. A key genomic difference between C. albicans and its less-virulent relatives, including its closest relative C. dubliniensis, is the unique expansion of the TLO (TeLOmere-associated) gene family in C. albicans. Individual Tlo proteins are fungal-specific subunits of Mediator, a large multi-subunit eukaryotic transcriptional co-activator complex. This amplification results in a large pool of ‘free,’ non-Mediator associated, Tlo protein present in C. albicans, but not in C. dubliniensis or other ascomycetes with attenuated virulence. We show that engineering a large ‘free’ pool of the C. dubliniensis Tlo2 (CdTlo2) protein in C. dubliniensis, through overexpression, results in a number of filamentation phenotypes typically associated only with C. albicans. The amplitude of these phenotypes is proportional to the amount of overexpressed CdTlo2 protein. Overexpression of other C. dubliniensis and C. albicans Tlo proteins do result in these phenotypes. Tlo proteins and their orthologs contain a Mediator interaction domain, and a potent transcriptional activation domain. Nuclear localization of the CdTlo2 activation domain, facilitated naturally by the Tlo Mediator binding domain or artificially through an appended nuclear localization signal, is sufficient for the CdTlo2 overexpression phenotypes. A C. albicans med3 null mutant causes multiple defects including the inability to localize Tlo proteins to the nucleus and reduced virulence in a murine systemic infection model. Our data supports a model in which the activation domain of ‘free’ Tlo protein competes with DNA bound transcription factors for targets that regulate key aspects of C. albicans cell physiology. The ascomycete fungus Candida albicans is a leading cause of hospital-acquired bloodstream infections in the United States. Due to limited anti-fungal drug options, there is an approximately 40% mortality rate and over 10,000 deaths per year associated with systemic C. albicans infections. It is unknown why C. albicans is the primary cause of systemic Candidiasis, versus related ascomycetes such as Candida dubliniensis. The genomes of C. albicans and C. dubliniensis are remarkably similar, yet C. dubliniensis has reduced virulence and exhibits less phenotypic plasticity. A striking genomic difference between the fungi is the amplification of the TLO (TeLOmere-associated) genes in C. albicans, which encode a fungal-specific subunit of the Mediator co-activator complex. Amplification results in a large pool of ‘free’ (non-Mediator associated) Tlo protein in C. albicans that is absent in C. dubliniensis. Engineering a large ‘free’ pool of Tlo protein in C. dubliniensis, through overexpression, results in phenotypes common in C. albicans, yet typically absent in C. dubliniensis. Tlo proteins contain a potent transcriptional activation domain. Nuclear localization of the Tlo activation domain is necessary and sufficient for the TLO overexpression phenotypes. This study provides a mechanistic explanation for how TLO amplification in C. albicans may enhance its virulence.
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影响因子：
6.7
作者：
Childers DS;Raziunaite I;Mol Avelar G;Mackie J;Budge S;Stead D;Gow NA;Lenardon MD;Ballou ER;MacCallum DM;Brown AJ
通讯作者：
Brown AJ
DOI：
10.3109/10409238.2015.1064854
发表时间：
2015
影响因子：
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