Sirtuins in the phylum Basidiomycota: A role in virulence in Cryptococcus neoformans.
Sirtuins in the phylum Basidiomycota: A role in virulence in Cryptococcus neoformans.
复制标题
DOI：
10.1038/srep46567
复制
发表时间：
2017-04-21
影响因子：
4.6
通讯作者：
Fraser JA
中科院分区：
文献类型：
--
作者：
Arras SDM;Chitty JL;Wizrah MSI;Erpf PE;Schulz BL;Tanurdzic M;Fraser JA
新型隐球菌的毒力受一系列转录因子的调控，并且还受到感染过程中获得适应性突变的影响。除了转录因子对毒力因子产生的时间调节和这些永久性的微进化变化之外，可遗传的表观遗传修饰（如组蛋白脱乙酰化）也可能在感染过程中发挥作用。在这里，我们描述了第一次全面分析的sirtuin类NAD+依赖组蛋白脱乙酰基酶的门担子菌，确定五个sirtuins编码的C。neoformans基因组。每个sirtuin基因都被删除，并进行了广泛的表型测试，以深入了解它们所起的潜在作用。考虑到沉默调节蛋白在其他物种中的多效性，令人惊讶的是，五种缺失菌株中只有两种在体外显示突变表型。然而，通过全细胞蛋白质组学鉴定了每种沉默调节蛋白丢失的神秘后果，并且小鼠感染揭示了SIR2、HST 3和HST 4在毒力中的作用。最有趣的表型是通过重新引入野生型基因而反复不能补充突变表型。这些数据支持的模型，调节sirtuin活性可能会使一个显着改变的表观遗传景观和毒力的C。新人类
Virulence of Cryptococcus neoformans is regulated by a range of transcription factors, and is also influenced by the acquisition of adaptive mutations during infection. Beyond the temporal regulation of virulence factor production by transcription factors and these permanent microevolutionary changes, heritable epigenetic modifications such as histone deacetylation may also play a role during infection. Here we describe the first comprehensive analysis of the sirtuin class of NAD+ dependent histone deacetylases in the phylum Basidiomycota, identifying five sirtuins encoded in the C. neoformans genome. Each sirtuin gene was deleted and a wide range of phenotypic tests performed to gain insight into the potential roles they play. Given the pleiotropic nature of sirtuins in other species, it was surprising that only two of the five deletion strains revealed mutant phenotypes in vitro. However, cryptic consequences of the loss of each sirtuin were identified through whole cell proteomics, and mouse infections revealed a role in virulence for SIR2, HST3 and HST4. The most intriguing phenotype was the repeated inability to complement mutant phenotypes through the reintroduction of the wild-type gene. These data support the model that regulation of sirtuin activity may be employed to enable a drastic alteration of the epigenetic landscape and virulence of C. neoformans.