MTL-independent phenotypic switching in Candida tropicalis and a dual role for Wor1 in regulating switching and filamentation.
MTL-independent phenotypic switching in Candida tropicalis and a dual role for Wor1 in regulating switching and filamentation.
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DOI：
10.1371/journal.pgen.1003369
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发表时间：
2013-03
期刊：
影响因子：
4.5
通讯作者：
Bennett RJ
中科院分区：
文献类型：
--
作者：
Porman AM;Hirakawa MP;Jones SK;Wang N;Bennett RJ
表型转换允许不同细胞状态之间的快速转变，对于病原真菌在不同宿主生态位的定殖和感染非常重要。在白色念珠菌中，白色不透明表型开关在调节性交配程序以及与哺乳动物宿主的相互作用中发挥着核心作用。白色-不透明切换由 MTL（类交配型）基因座编码的基因控制，确保只有 a 或 α 细胞可以从白色状态切换到可交配的不透明状态，而 a/α 细胞难以切换。在这里，我们发现相关病原体热带念珠菌在所有三种细胞类型（a、α和a/α）中经历白色不透明转换，因此转换独立于MTL控制。我们还证明热带念珠菌白细胞本身具有交配能力，尽管其效率低于不透明细胞。热带念珠菌白色和不透明细胞的转录谱揭示了 MTL 纯合子和 MTL 杂合细胞中开关调节基因之间的显着重叠，尽管 a/α 细胞中白色不透明调节的基因数量是 a 细胞中的两倍。在白色念珠菌中，转录因子 Wor1 是白色不透明开关的主要调节因子，我们发现 Wor1 也在热带念珠菌中调节开关。 WOR1 的缺失将 a、α 和 a/α 细胞锁定在白色状态，而 WOR1 过表达则诱导这些细胞采用不透明状态。此外，我们发现 WOR1 过表达促进热带念珠菌丝状生长和生物膜形成，与白色不透明开关无关。这些结果表明热带念珠菌 Wor1 的作用扩大，包括调节哺乳动物宿主感染所需的过程。我们根据 Wor1 作为酵母形式和丝状生长之间转变的转录调节因子的祖先作用来讨论这些发现。白色不透明表型开关在人类真菌病原体白色念珠菌中得到了广泛的表征，它在调节进入有性生殖方面发挥着核心作用。这种表观遗传开关受到 MTL 基因座的严格调控，因此只有 a 或 α 细胞类型可以切换到不透明状态，而 a/α 细胞则锁定在白色状态。相比之下，我们表明，在相关病原体热带念珠菌中，白细胞能够进行有性交配，并且白色不透明开关独立于 MTL 控制。因此，MTL a、α和a/α细胞都经历白色和不透明状态之间的可逆转换。尽管存在这些差异，热带念珠菌和白色念珠菌的转换都依赖于 Wor1 转录因子的表达。该因子在真菌子囊菌中是保守的，并且在一些物种中充当酵母向丝状体转变的主要调节因子。我们发现，除了调节热带念珠菌中的白色不透明开关之外，Wor1 表达还促进该物种的丝状化和生物膜形成。因此，我们认为热带念珠菌 Wor1 保留了该转录因子家族的祖先作用，同时还获得了对最近进化的白色不透明表型开关的控制。
Phenotypic switching allows for rapid transitions between alternative cell states and is important in pathogenic fungi for colonization and infection of different host niches. In Candida albicans, the white-opaque phenotypic switch plays a central role in regulating the program of sexual mating as well as interactions with the mammalian host. White-opaque switching is controlled by genes encoded at the MTL (mating-type-like) locus that ensures that only a or α cells can switch from the white state to the mating-competent opaque state, while a/α cells are refractory to switching. Here, we show that the related pathogen C. tropicalis undergoes white-opaque switching in all three cell types (a, α, and a/α), and thus switching is independent of MTL control. We also demonstrate that C. tropicalis white cells are themselves mating-competent, albeit at a lower efficiency than opaque cells. Transcriptional profiling of C. tropicalis white and opaque cells reveals significant overlap between switch-regulated genes in MTL homozygous and MTL heterozygous cells, although twice as many genes are white-opaque regulated in a/α cells as in a cells. In C. albicans, the transcription factor Wor1 is the master regulator of the white-opaque switch, and we show that Wor1 also regulates switching in C. tropicalis; deletion of WOR1 locks a, α, and a/α cells in the white state, while WOR1 overexpression induces these cells to adopt the opaque state. Furthermore, we show that WOR1 overexpression promotes both filamentous growth and biofilm formation in C. tropicalis, independent of the white-opaque switch. These results demonstrate an expanded role for C. tropicalis Wor1, including the regulation of processes necessary for infection of the mammalian host. We discuss these findings in light of the ancestral role of Wor1 as a transcriptional regulator of the transition between yeast form and filamentous growth. The white-opaque phenotypic switch has been extensively characterized in the human fungal pathogen Candida albicans, where it plays a central role in regulating entry into sexual reproduction. This epigenetic switch is strictly regulated by the MTL locus so that only a or α cell types can switch to the opaque state, whereas a/α cells are locked in the white state. In contrast, we show that in the related pathogen C. tropicalis white cells are capable of sexual mating and that the white-opaque switch is independent of MTL control. Thus, MTL a, α, and a/α cells all undergo reversible switching between white and opaque states. Despite these differences, switching in both C. tropicalis and C. albicans is dependent on the expression of the Wor1 transcription factor. This factor is conserved amongst fungal ascomycetes and, in several species, acts as a master regulator of the yeast-to-filament transition. We show that, in addition to regulating the white-opaque switch in C. tropicalis, Wor1 expression also promotes filamentation and biofilm formation in this species. We therefore propose that C. tropicalis Wor1 has retained the ancestral role of this family of transcription factors while also gaining control over the more recently evolved white-opaque phenotypic switch.