Hsp90 orchestrates temperature-dependent Candida albicans morphogenesis via Ras1-PKA signaling.
Hsp90 orchestrates temperature-dependent Candida albicans morphogenesis via Ras1-PKA signaling.
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DOI：
10.1016/j.cub.2009.03.017
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发表时间：
2009-04-28
期刊：
影响因子：
--
通讯作者：
Cowen LE
中科院分区：
文献类型：
--
作者：
Shapiro RS;Uppuluri P;Zaas AK;Collins C;Senn H;Perfect JR;Heitman J;Cowen LE
Hsp90 是一种环境相关的分子伴侣，影响细胞信号传导的多种调节因子的形式和功能。 Hsp90 通过促进关键的细胞应激反应来增强真菌耐药性的进化。在这里，我们证明，在人类主要的真菌病原体白色念珠菌中，Hsp90 控制着细胞回路，该回路不仅是耐药性所需的，而且也是从酵母到丝状生长的关键形态发生转变所需的，而丝状生长对毒力至关重要。这种转变通常受到环境因素的调节，例如暴露于血清，这取决于升高的温度以诱导形态发生。这种温度依赖性的基础仍然是个谜。我们发现，在没有外部提示的情况下，在药理学或遗传上损害 Hsp90 功能会诱导从酵母菌向丝状生长的转变。升高温度可缓解 Hsp90 介导的形态发生程序抑制。 Hsp90 通过抑制 Ras1-PKA 信号传导来调节形态发生电路。适度的 Hsp90 妥协增强了激活的 Ras1 信号传导的表型效应，而 Ras1-PKA 级联的正调节因子的缺失则阻断了对 Hsp90 抑制的形态发生反应。与毒力形态发生灵活性的要求一致，白色念珠菌 Hsp90 的消耗可减弱全身性疾病小鼠模型中的毒力。 Hsp90 控制环境信号与细胞信号传导的整合，以协调真菌形态发生和毒力，为危及生命的传染病提出新的治疗策略。 Hsp90 控制响应温度变化的关键发育程序的能力提供了一种新机制，补充了生物体用来感知温度的优雅功能。
Hsp90 is an environmentally contingent molecular chaperone that influences the form and function of diverse regulators of cellular signaling. Hsp90 potentiates the evolution of fungal drug resistance by enabling crucial cellular stress responses. Here we demonstrate that in the leading fungal pathogen of humans, Candida albicans, Hsp90 governs cellular circuitry required not only for drug resistance but also for the key morphogenetic transition from yeast to filamentous growth that is crucial for virulence. This transition is normally regulated by environmental cues, such as exposure to serum, that are contingent upon elevated temperature to induce morphogenesis. The basis for this temperature dependence has remained enigmatic. We show that compromising Hsp90 function pharmacologically or genetically induces a transition from yeast to filamentous growth in the absence of external cues. Elevated temperature relieves Hsp90-mediated repression of the morphogenetic program. Hsp90 regulates morphogenetic circuitry by repressing Ras1-PKA signaling. Modest Hsp90 compromise enhances the phenotypic effects of activated Ras1 signaling while deletion of positive regulators of the Ras1-PKA cascade blocks the morphogenetic response to Hsp90 inhibition. Consistent with the requirement for morphogenetic flexibility for virulence, depletion of C. albicans Hsp90 attenuates virulence in a murine model of systemic disease. Hsp90 governs the integration of environmental cues with cellular signaling to orchestrate fungal morphogenesis and virulence, suggesting new therapeutic strategies for life-threatening infectious disease. Hsp90’s capacity to govern a key developmental program in response to temperature change provides a new mechanism that complements the elegant repertoire that organisms utilize to sense temperature.
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