The Hsp90 co-chaperone Sgt1 governs Candida albicans morphogenesis and drug resistance.
The Hsp90 co-chaperone Sgt1 governs Candida albicans morphogenesis and drug resistance.
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DOI：
10.1371/journal.pone.0044734
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Cowen LE
中科院分区：
文献类型：
--
作者：
Shapiro RS;Zaas AK;Betancourt-Quiroz M;Perfect JR;Cowen LE
分子伴侣Hsp 90协调控制真菌形态发生、生物膜发育、耐药性和毒力的调节电路。热休克蛋白90的功能与合作分子伴侣，以调节稳定性和激活的客户蛋白，其中许多是信号转导。在这里，我们描述了人类主要真菌病原体白色念珠菌中的第一个Hsp 90共伴侣蛋白。我们证明了Sgt 1与Hsp 90的物理相互作用，并且它支配C。白念珠菌形态发生和耐药性。Sgt 1表型的遗传缺失导致Hsp 90的缺失，诱导酵母丝状形态发生和侵入性生长。Sgt 1通过桥接两个形态发生调节因子来控制这些性状：Hsp 90和cAMP-PKA信号级联的腺苷酸环化酶Cyr 1。Sgt 1与Cyr 1发生物理相互作用，Sgt 1或Hsp 90的缺失激活cAMP-PKA信号传导，揭示了Hsp 90与PKA信号级联之间难以捉摸的联系。sgt 1还介导对两种最广泛使用的抗真菌药物唑类和棘白菌素类的耐受性和耐药性。Sgt 1的缺失消除了对靶向细胞膜的唑类的基础耐受性和获得性抗性。Sgt 1的缺失也消除了对棘白菌素的耐受性和抗性，棘白菌素靶向细胞壁，并使棘白菌素具有杀真菌性。虽然Sgt 1和Hsp 90对耐药性有保守的影响，但其潜在机制是不同的。热休克蛋白90的消耗不稳定的客户端蛋白钙调神经磷酸酶，从而阻断药物诱导的应激反应的关键;相反，Sgt 1的消耗不稳定的钙调神经磷酸酶，但阻断钙调神经磷酸酶激活响应药物诱导的应激。Sgt 1不仅影响形态发生和耐药性，而且还影响致病性，如C.白色念珠菌Sgt 1导致系统性感染小鼠模型中肾脏真菌负荷降低。因此，我们对真菌病原体中第一个Hsp 90共伴侣的表征建立了C.白念珠菌Sgt 1作为一种形态发生和耐药性的全球调节因子，为治疗危及生命的真菌感染提供了新的靶点。
The molecular chaperone Hsp90 orchestrates regulatory circuitry governing fungal morphogenesis, biofilm development, drug resistance, and virulence. Hsp90 functions in concert with co-chaperones to regulate stability and activation of client proteins, many of which are signal transducers. Here, we characterize the first Hsp90 co-chaperone in the leading human fungal pathogen, Candida albicans. We demonstrate that Sgt1 physically interacts with Hsp90, and that it governs C. albicans morphogenesis and drug resistance. Genetic depletion of Sgt1 phenocopies depletion of Hsp90, inducing yeast to filament morphogenesis and invasive growth. Sgt1 governs these traits by bridging two morphogenetic regulators: Hsp90 and the adenylyl cyclase of the cAMP-PKA signaling cascade, Cyr1. Sgt1 physically interacts with Cyr1, and depletion of either Sgt1 or Hsp90 activates cAMP-PKA signaling, revealing the elusive link between Hsp90 and the PKA signaling cascade. Sgt1 also mediates tolerance and resistance to the two most widely deployed classes of antifungal drugs, azoles and echinocandins. Depletion of Sgt1 abrogates basal tolerance and acquired resistance to azoles, which target the cell membrane. Depletion of Sgt1 also abrogates tolerance and resistance to echinocandins, which target the cell wall, and renders echinocandins fungicidal. Though Sgt1 and Hsp90 have a conserved impact on drug resistance, the underlying mechanisms are distinct. Depletion of Hsp90 destabilizes the client protein calcineurin, thereby blocking crucial responses to drug-induced stress; in contrast, depletion of Sgt1 does not destabilize calcineurin, but blocks calcineurin activation in response to drug-induced stress. Sgt1 influences not only morphogenesis and drug resistance, but also virulence, as genetic depletion of C. albicans Sgt1 leads to reduced kidney fungal burden in a murine model of systemic infection. Thus, our characterization of the first Hsp90 co-chaperone in a fungal pathogen establishes C. albicans Sgt1 as a global regulator of morphogenesis and drug resistance, providing a new target for treatment of life-threatening fungal infections.
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影响因子：
64.8
作者：
Chen, Guangbo;Bradford, William D.;Seidel, Chris W.;Li, Rong
通讯作者：
Li, Rong
影响因子：
4.5
作者：
Diezmann S;Michaut M;Shapiro RS;Bader GD;Cowen LE
通讯作者：
Cowen LE
影响因子：
3.3
作者：
Bachewich, C;Thomas, DY;Whiteway, M
通讯作者：
Whiteway, M
影响因子：
3.6
作者：
Fang, Hao-Ming;Wang, Yue
通讯作者：
Wang, Yue
DOI：
10.1073/pnas.90.24.11558
发表时间：
1993-12-15
影响因子：
11.1
作者：
BALDAUF, SL;PALMER, JD
通讯作者：
PALMER, JD