酵母中熱誘導型Hsp90蛋白的各個結構域的結構圖。頂端是二聚體Hsp90的晶體結構,，結合到二聚體上的ATP分子用空間填充球表示,。底部是酵母Hsp90蛋白的一維序列。NTD=N端結構域(紅色),，MD=中間結構域(綠色),，CTD=C端結構域(藍色)。圖片來自維基共享資源,。
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白色念珠菌(Candida albicans)通常都是無害的真菌,，在所有人身上都存在。但在不同的遺傳和環(huán)境條件下,，它變成傳染性的真菌,，在這種轉變當中溫度是一個關鍵性決定因素。它產生的感染可以是溫和的,，比如持續(xù)的陰道或腸道感染,，也可以是比較嚴重的，比如AIDS患者或者接受化療的病人全身性的而且是潛在致命性的血液感染,。
2009年,，加拿大多倫多大學分子遺傳學系教授Leah Cowen首次繪制的白色念珠菌分子作用機制[1]表明這種真菌的生長與一種“分子伴侶”熱休克蛋白90(heat-shock protein 90, Hsp90)的功能緊密相關。如今,，根據2012年3月20日發(fā)表在《細胞》子刊Current Biology期刊上的一篇論文,，Cowen教授和她的同事們詳細描述另一種機制：白色念珠菌通過蛋白Hms1與一種周期素Pcl1及其搭檔周期素依賴性蛋白激酶(cyclin-dependent kinase)Pho85協同作用來控制它對溫度升高而作出的反應。這種途徑從根本上影響白色念珠菌如何感知溫度,。
研究人員還證實剔除Hms1能夠抑制白色念珠菌感染,，從而給出一種可能的臨床療法。
在發(fā)現Hms1途徑影響白色念珠菌生長和發(fā)育以及了解通過Hsp90作用途徑發(fā)揮功能的其他關鍵性調節(jié)物之后,，Cowen教授和她的實驗室猜測還有更多的調節(jié)性蛋白尚待發(fā)現,，于是便在另一項研究中研究其他的作用途徑和與Hsp90發(fā)生相互作用的蛋白。
通過和多倫多大學唐納利細胞與生物分子研究中心(Donnelly Centre for Cellular and Biomolecular Research)的Gary Bader教授合作,，Cowen教授領導的研究小組通過一種“化學基因組學(chemical genomics)”的方法描繪了一幅更加龐大的與Hsp90發(fā)生相互作用的分子伴侶網絡，而且人們之前從沒有將這種方法應用于白色念珠菌,。他們的研究結果于2012年3月16日發(fā)表在期刊PLoS Genetics上,，鑒定出在各種條件(如不同的溫度和暴露在抗真菌藥物中)下226種與Hsp90相互作用的分子,。在這些相互作用中，有224種是以前未知的,。這樣,，研究人員就擁有大量新的作用靶標，而且Hsp90通過這些靶標應當能夠調控白色念珠菌的形態(tài)發(fā)生和抗藥性產生,。
白色念珠菌(Candida albicans)Hsp90蛋白遺傳性相互作用網絡,。
此外，研究人員從他們的研究中總結出幾個控制Hsp90分子伴侶網絡的預測性規(guī)則(predictive rule),。一些與Hsp90相互作用的分子只在一小部分脅迫條件(stress condition)下發(fā)揮著重要作用,，這意味著它們很可能是在Hsp90調控的特定細胞過程的“下游”發(fā)揮功能。其他的相互作用分子在很多種脅迫條件下發(fā)揮重要作用,，這意味著它們很可能是在Hsp90在調控它自身功能的上游發(fā)揮作用,。
Cowen說，“Hsp90能夠穩(wěn)定很多種蛋白,，但是之前沒有人預測哪些分子成為Hsp90的作用對象,。因此我們利用這種分子伴侶網絡來開展這種預測所得到的研究結果確實很好和出乎意料之外。” (生物谷：towersimper編譯)
[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>
