Department of Biological Chemistry, University of California, Irvine, California, United States of America.
PLoS Biol. 2011 Jul;9(7):e1001105. doi: 10.1371/journal.pbio.1001105. Epub 2011 Jul 19.
Phenotypic plasticity is common in development. For Candida albicans, the most common cause of invasive fungal infections in humans, morphological plasticity is its defining feature and is critical for its pathogenesis. Unlike other fungal pathogens that exist primarily in either yeast or hyphal forms, C. albicans is able to switch reversibly between yeast and hyphal growth forms in response to environmental cues. Although many regulators have been found involved in hyphal development, the mechanisms of regulating hyphal development and plasticity of dimorphism remain unclear. Here we show that hyphal development involves two sequential regulations of the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of the Nrg1 transcriptional repressor of hyphal morphogenesis via activation of the cAMP-PKA pathway. Maintenance requires promoter recruitment of Hda1 histone deacetylase under reduced Tor1 (target of rapamycin) signaling. Hda1 deacetylates a subunit of the NuA4 histone acetyltransferase module, leading to eviction of the NuA4 acetyltransferase module and blockage of Nrg1 access to promoters of hypha-specific genes. Promoter recruitment of Hda1 for hyphal maintenance happens only during the period when Nrg1 is gone. The sequential regulation of hyphal development by the activation of the cAMP-PKA pathway and reduced Tor1 signaling provides a molecular mechanism for plasticity of dimorphism and how C. albicans adapts to the varied host environments in pathogenesis. Such temporally linked regulation of promoter chromatin by different signaling pathways provides a unique mechanism for integrating multiple signals during development and cell fate specification.
表型可塑性在发育中很常见。对于白色念珠菌，这是人类最常见的侵袭性真菌感染的原因，形态可塑性是其定义特征，对其发病机制至关重要。与其他主要存在于酵母或菌丝形式的真菌病原体不同，白色念珠菌能够根据环境线索可逆地在酵母和菌丝生长形式之间切换。尽管已经发现许多调节剂参与了菌丝发育，但调节菌丝发育和二态性可塑性的机制仍不清楚。在这里，我们表明菌丝发育涉及菌丝特异性基因启动子染色质的两个连续调节。起始需要通过激活 cAMP-PKA 途径快速但暂时消除菌丝形态发生的 Nrg1 转录抑制剂。维持需要在 Tor1（雷帕霉素靶蛋白）信号降低的情况下招募 Hda1 组蛋白去乙酰化酶到启动子上。Hda1 去乙酰化 NuA4 组蛋白乙酰转移酶模块的一个亚基，导致 NuA4 乙酰转移酶模块的驱逐和 Nrg1 无法访问菌丝特异性基因的启动子。仅在 Nrg1 消失期间，Hda1 才能募集到启动子以维持菌丝。cAMP-PKA 途径的激活和 Tor1 信号降低对菌丝发育的顺序调节为二态性可塑性以及白色念珠菌如何适应发病机制中宿主环境的多样性提供了分子机制。不同信号通路对启动子染色质的这种时间相关调节为发育和细胞命运特化过程中整合多个信号提供了独特的机制。
