酵母中热诱导型Hsp90蛋白的各个结构域的结构图。顶端是二聚体Hsp90的晶体结构，结合到二聚体上的ATP分子用空间填充球表示。底部是酵母Hsp90蛋白的一维序列。NTD=N端结构域(红色)，MD=中间结构域(绿色)，CTD=C端结构域(蓝色)。图片来自维基共享资源。
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白色念珠菌(Candida albicans)通常都是无害的真菌，在所有人身上都存在。但在不同的遗传和环境条件下，它变成传染性的真菌，在这种转变当中温度是一个关键性决定因素。它产生的感染可以是温和的，比如持续的阴道或肠道感染，也可以是比较严重的，比如AIDS患者或者接受化疗的病人全身性的而且是潜在致命性的血液感染。
2009年，加拿大多伦多大学分子遗传学系教授Leah Cowen首次绘制的白色念珠菌分子作用机制[1]表明这种真菌的生长与一种“分子伴侣”热休克蛋白90(heat-shock protein 90, Hsp90)的功能紧密相关。如今，根据2012年3月20日发表在《细胞》子刊Current Biology期刊上的一篇论文，Cowen教授和她的同事们详细描述另一种机制：白色念珠菌通过蛋白Hms1与一种周期素Pcl1及其搭档周期素依赖性蛋白激酶(cyclin-dependent kinase)Pho85协同作用来控制它对温度升高而作出的反应。这种途径从根本上影响白色念珠菌如何感知温度。
研究人员还证实剔除Hms1能够抑制白色念珠菌感染，从而给出一种可能的临床疗法。
在发现Hms1途径影响白色念珠菌生长和发育以及了解通过Hsp90作用途径发挥功能的其他关键性调节物之后，Cowen教授和她的实验室猜测还有更多的调节性蛋白尚待发现，于是便在另一项研究中研究其他的作用途径和与Hsp90发生相互作用的蛋白。
通过和多伦多大学唐纳利细胞与生物分子研究中心(Donnelly Centre for Cellular and Biomolecular Research)的Gary Bader教授合作，Cowen教授领导的研究小组通过一种“化学基因组学(chemical genomics)”的方法描绘了一幅更加庞大的与Hsp90发生相互作用的分子伴侣网络，而且人们之前从没有将这种方法应用于白色念珠菌。他们的研究结果于2012年3月16日发表在期刊PLoS Genetics上，鉴定出在各种条件(如不同的温度和暴露在抗真菌药物中)下226种与Hsp90相互作用的分子。在这些相互作用中，有224种是以前未知的。这样，研究人员就拥有大量新的作用靶标，而且Hsp90通过这些靶标应当能够调控白色念珠菌的形态发生和抗药性产生。
白色念珠菌(Candida albicans)Hsp90蛋白遗传性相互作用网络。
此外，研究人员从他们的研究中总结出几个控制Hsp90分子伴侣网络的预测性规则(predictive rule)。一些与Hsp90相互作用的分子只在一小部分胁迫条件(stress condition)下发挥着重要作用，这意味着它们很可能是在Hsp90调控的特定细胞过程的“下游”发挥功能。其他的相互作用分子在很多种胁迫条件下发挥重要作用，这意味着它们很可能是在Hsp90在调控它自身功能的上游发挥作用。
Cowen说，“Hsp90能够稳定很多种蛋白，但是之前没有人预测哪些分子成为Hsp90的作用对象。因此我们利用这种分子伴侣网络来开展这种预测所得到的研究结果确实很好和出乎意料之外。” (生物谷：towersimper编译)
[1] Rebecca S. Shapiro et al.. Hsp90 Orchestrates Temperature-Dependent Candida albicans Morphogenesis via Ras1-PKA Signaling. Current Biology, Volume 19, Issue 8, 621-629, 26 March 2009, doi:10.1016/j.cub.2009.03.017.
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doi:10.1016/j.cub.2012.01.062
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Pho85, Pcl1, and Hms1 Signaling Governs Candida albicans Morphogenesis Induced by High Temperature or Hsp90 Compromise
Rebecca S. Shapiro, Adnane Sellam, Faiza Tebbji, Malcolm Whiteway, Andre Nantel, Leah E. Cowen
Background Temperature exerts powerful control over development and virulence of diverse pathogens. In the leading human fungal pathogen, Candida albicans, temperature governs morphogenesis, a key virulence trait. Many cues that induce the yeast to filament transition are contingent on a minimum of 37°C, whereas further elevation to 39°C serves as an independent inducer. The molecular chaperone Hsp90 is a key regulator of C. albicans temperature-dependent morphogenesis. Compromise of Hsp90 function genetically, pharmacologically, or by elevated temperature induces filamentation in a manner that depends on protein kinase A signaling but is independent of the terminal transcription factor, Efg1.
Results Here, we establish that despite morphological and regulatory differences, inhibition of Hsp90 induces a transcriptional profile similar to that induced by other filamentation cues and does so independently of Efg1. Further, we identify Hms1 as a transcriptional regulator required for morphogenesis induced by elevated temperature or Hsp90 compromise. Hms1 functions downstream of the cyclin Pcl1 and the cyclin-dependent kinase Pho85, both of which are required for temperature-dependent filamentation. Upon Hsp90 inhibition, Hms1 binds to DNA elements involved in filamentous growth, including UME6 and RBT5, and regulates their expression, providing a mechanism through which Pho85, Pcl1, and Hms1 govern morphogenesis. Consistent with the importance of morphogenetic flexibility for virulence, deletion of C. albicans HMS1 attenuates virulence in a metazoan model of infection.
Conclusions Thus, we establish a new mechanism through which Hsp90 orchestrates C. albicans morphogenesis, and define novel regulatory circuitry governing a temperature-dependent developmental program, with broad implications for temperature sensing and virulence of microbial pathogens.
doi:10.1371/journal.pgen.1002562
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Mapping the Hsp90 Genetic Interaction Network in Candida albicans Reveals Environmental Contingency and Rewired Circuitry
Stephanie Diezmann, Magali Michaut, Rebecca S. Shapiro, Gary D. Bader, Leah E. Cowen
THE evolutionary over rewiring network and Hsp90, of downstream upstream effectors novel pathogen, fungal a chaperone first the in contingency environmental establish We Ahr1. factor transcription CK2 kinase protein with as operate to poised are these environments, many growth for important interactors Few Hog1. MAPK they that suggesting conditions, specific under only genetic 226 most contingent, environmentally is The conditions. stress diverse interaction Hsp90 albicans C. mapped we approach, genomic chemical Utilizing humans. pathogen leading albicans, Candida identified been have interactions two while cerevisiae, Saccharomyces yeast model proteome ~10% interacts evolution. resistance, drug development, influences fungi, In circuitry. cellular affecting profoundly eukaryotes, all transducers signal folding regulates molecular>
