Mapping the Hsp90 genetic interaction network in Candida albicans reveals environmental contingency and rewired circuitry.
Mapping the Hsp90 genetic interaction network in Candida albicans reveals environmental contingency and rewired circuitry.
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DOI：
10.1371/journal.pgen.1002562
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Cowen LE
中科院分区：
文献类型：
--
作者：
Diezmann S;Michaut M;Shapiro RS;Bader GD;Cowen LE
分子伴侣Hsp90调节所有真核生物中各种信号转导的折叠，深刻影响细胞电路。在真菌中，Hsp90影响发育、耐药和进化。Hsp90与酿酒酵母菌模型中约10%的蛋白质组相互作用，而在人类主要真菌病原体白色念珠菌中仅鉴定出两种相互作用。利用化学基因组学方法，我们绘制了不同胁迫条件下白色念珠菌Hsp90相互作用网络。伴侣网络是环境偶然的，226个遗传相互作用因子中的大多数仅在特定条件下对生长重要，这表明它们与MAPK Hog1一样在Hsp90的下游运作。在许多环境中，很少有相互作用因子对生长很重要，这些相互作用因子在Hsp90的上游起作用，如蛋白激酶CK2和转录因子Ahr1。我们在真菌病原体的第一个伴侣网络、Hsp90上游和下游的新效应物以及网络在进化时间中的重新连接中建立了环境偶然性。Hsp90是真核生物中一种重要的保守分子伴侣蛋白，它协助折叠多种蛋白质，尤其是细胞信号的调节因子。通过激活响应环境信号的信号，Hsp90对生物学的许多方面有着深远的影响。在真菌中，Hsp90影响发育、耐药和进化。在酿酒酵母菌模型中，Hsp90与约10%的蛋白质相互作用。在主要的人类真菌病原体白色念珠菌中，只发现了两种相互作用。我们进行了化学遗传筛选，以阐明不同胁迫条件下白色念珠菌Hsp90相互作用网络。226个遗传相互作用因子中的大多数对特定条件下的生长很重要，这表明它们作用于Hsp90的下游，并且该网络是环境偶然的。例如，激酶Hog1依赖于Hsp90的激活。在许多条件下，只有少数相互作用因子对生长是重要的，这表明它们作用于Hsp90的上游。例如，蛋白激酶CK2调节Hsp90伴侣机器的功能，转录因子Ahr1控制Hsp90的表达。因此，我们确定了Hsp90上游和下游的新效应物，并建立了真菌病原体的第一个伴侣网络，并提供了环境偶然性和网络在进化时间中的重新连接的证据。
The molecular chaperone Hsp90 regulates the folding of diverse signal transducers in all eukaryotes, profoundly affecting cellular circuitry. In fungi, Hsp90 influences development, drug resistance, and evolution. Hsp90 interacts with ∼10% of the proteome in the model yeast Saccharomyces cerevisiae, while only two interactions have been identified in Candida albicans, the leading fungal pathogen of humans. Utilizing a chemical genomic approach, we mapped the C. albicans Hsp90 interaction network under diverse stress conditions. The chaperone network is environmentally contingent, and most of the 226 genetic interactors are important for growth only under specific conditions, suggesting that they operate downstream of Hsp90, as with the MAPK Hog1. Few interactors are important for growth in many environments, and these are poised to operate upstream of Hsp90, as with the protein kinase CK2 and the transcription factor Ahr1. We establish environmental contingency in the first chaperone network of a fungal pathogen, novel effectors upstream and downstream of Hsp90, and network rewiring over evolutionary time. Hsp90 is an essential and conserved molecular chaperone in eukaryotes that assists with folding diverse proteins, especially regulators of cellular signaling. By activating signaling in response to environmental cues, Hsp90 has a profound impact on myriad aspects of biology. In fungi, Hsp90 influences development, drug resistance, and evolution. In the model yeast Saccharomyces cerevisiae, Hsp90 interacts with ∼10% of proteins. In the leading human fungal pathogen, Candida albicans, only two interactions have been identified. We conducted a chemical genetic screen to elucidate the C. albicans Hsp90 interaction network under diverse stress conditions. The majority of the 226 genetic interactors are important for growth under specific conditions, suggesting that they act downstream of Hsp90 and that the network is environmentally contingent. For example, the kinase Hog1 depends upon Hsp90 for activation. Only a few interactors are important for growth in many conditions, suggesting that they act upstream of Hsp90. For example, the protein kinase CK2 regulates function of the Hsp90 chaperone machine and the transcription factor Ahr1 governs HSP90 expression. Thus, we identify novel effectors upstream and downstream of Hsp90, and establish the first chaperone network of a fungal pathogen, with evidence for environmental contingency and network rewiring over evolutionary time.
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