Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin.
Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin.
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DOI：
10.1371/journal.ppat.1000532
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发表时间：
2009-07
期刊：
影响因子：
6.7
通讯作者：
Cowen LE
中科院分区：
文献类型：
--
作者：
Singh SD;Robbins N;Zaas AK;Schell WA;Perfect JR;Cowen LE
白色念珠菌是人类的主要真菌病原体，在免疫功能低下的人中会导致危及生命的疾病。抗真菌药物的数量有限阻碍了念珠菌病的治疗，这些药物的疗效受到宿主毒性、抑菌活性和出现耐药性的影响。我们先前已经证实，分子伴侣Hsp90，它调节各种客户蛋白的形式和功能，在白色念珠菌和模式酵母中增强对氮唑类化合物的抗药性。酿酒酵母的遗传学研究表明，热休克蛋白90的S在唑类耐药中的作用是通过客户蛋白钙调神经磷酸酶使细胞对氮唑类药物施加的膜胁迫做出关键反应。在这里，我们证明了Hsp90控制着对几十年来唯一进入临床的新型抗真菌药物棘球菌素的耐药性所需的细胞电路，棘球菌素可以抑制真菌细胞壁关键成分的生物合成。Hsp90功能的药理或遗传损伤降低了白念珠菌实验室菌株的耐受性和临床分离株对棘球菌素的耐药性，并产生了一种杀菌组合。表现为钙调神经磷酸酶功能受损，Hsp90功能受损。我们证实了钙调神经磷酸酶是白色念珠菌中的一种Hsp90客户蛋白：相互免疫共沉淀证实了物理相互作用；抑制Hsp90抑制了钙调神经磷酸酶的激活；当Hsp90基因减少时，钙调神经磷酸酶水平被耗尽。钙调神经磷酸酶下游效应子Crz1在介导棘球蛋白激活的钙调神经磷酸酶依赖的应激反应中起部分作用。热休克蛋白90的S在棘球菌素耐药中的作用具有治疗潜力，因为白念珠菌热休克蛋白90表达的遗传妥协增强了棘球菌素在播散性念珠菌病小鼠模型中的疗效。我们的结果在白色念珠菌中发现了第一个Hsp90客户蛋白，确立了Hsp90在介导棘球菌素耐药性方面的全新角色，并证明了靶向Hsp90为治疗威胁生命的真菌疾病提供了一种有前途的治疗策略。真菌病原体对免疫系统受损的人构成严重威胁。在机会性真菌病原体中，最主要的是白色念珠菌。白念珠菌感染的治疗仍然具有挑战性，因为有效的药物很少，而且这种病原体已经进化出许多策略来在药物暴露中生存下来。棘球菌素是几十年来进入临床的唯一一类新的抗真菌药物，它们阻止真菌细胞壁的一种重要成分的生物合成。我们发现，分子伴侣Hsp90是其客户蛋白在细胞中折叠和发挥功能所必需的，它控制着白色念珠菌暴露于棘球菌素后存活的能力。Hsp90功能的妥协使棘球菌素更有效地杀灭白色念珠菌实验室菌株和临床分离株。HSP90通过启用其客户蛋白钙调神经磷酸酶的功能来协调对棘球菌素施加的细胞壁压力的关键反应，钙调神经磷酸酶使真菌能够在其他致命的条件下存活。我们的结果表明，损害Hsp90的功能提供了一个强大而迫切需要的策略，使现有的抗真菌药物在治疗危及生命的真菌感染方面更加有效。
Candida albicans is the leading fungal pathogen of humans, causing life-threatening disease in immunocompromised individuals. Treatment of candidiasis is hampered by the limited number of antifungal drugs whose efficacy is compromised by host toxicity, fungistatic activity, and the emergence of drug resistance. We previously established that the molecular chaperone Hsp90, which regulates the form and function of diverse client proteins, potentiates resistance to the azoles in C. albicans and in the model yeast Saccharomyces cerevisiae. Genetic studies in S. cerevisiae revealed that Hsp90's role in azole resistance is to enable crucial cellular responses to the membrane stress exerted by azoles via the client protein calcineurin. Here, we demonstrate that Hsp90 governs cellular circuitry required for resistance to the only new class of antifungals to reach the clinic in decades, the echinocandins, which inhibit biosynthesis of a critical component of the fungal cell wall. Pharmacological or genetic impairment of Hsp90 function reduced tolerance of C. albicans laboratory strains and resistance of clinical isolates to the echinocandins and created a fungicidal combination. Compromising calcineurin function phenocopied compromising Hsp90 function. We established that calcineurin is an Hsp90 client protein in C. albicans: reciprocal co-immunoprecipitation validated physical interaction; Hsp90 inhibition blocked calcineurin activation; and calcineurin levels were depleted upon genetic reduction of Hsp90. The downstream effector of calcineurin, Crz1, played a partial role in mediating calcineurin-dependent stress responses activated by echinocandins. Hsp90's role in echinocandin resistance has therapeutic potential given that genetic compromise of C. albicans HSP90 expression enhanced the efficacy of an echinocandin in a murine model of disseminated candidiasis. Our results identify the first Hsp90 client protein in C. albicans, establish an entirely new role for Hsp90 in mediating resistance to echinocandins, and demonstrate that targeting Hsp90 provides a promising therapeutic strategy for the treatment of life-threatening fungal disease. Fungal pathogens pose a serious threat to people with compromised immune systems. Chief among the opportunistic fungal pathogens is Candida albicans. Treatment of C. albicans infections remains challenging because there are very few effective drugs and the pathogen has evolved many strategies to survive drug exposure. The echinocandins are the only new class of antifungal drug to reach the clinic in decades and they block biosynthesis of an essential component of the fungal cell wall. We discovered that the molecular chaperone Hsp90, which is required for its client proteins in the cell to fold and function, governs the ability of C. albicans to survive exposure to echinocandins. Compromising Hsp90 function renders the echinocandins more effective at killing C. albicans laboratory strains and clinical isolates. Hsp90 orchestrates the crucial responses to cell wall stress exerted by the echinocandins by enabling the function of its client protein calcineurin, which allows the fungus to survive otherwise lethal conditions. Our results suggest that compromising Hsp90 function provides a powerful and much-needed strategy to render existing antifungal drugs more effective in the treatment of life-threatening fungal infections.
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影响因子：
4.9
作者：
Markovich, S;Yekutiel, A;Osherov, N
通讯作者：
Osherov, N
影响因子：
3.1
作者：
Onyewu, Chiatogu;Wormley, Floyd L. Jr;Heitman, Joseph
通讯作者：
Heitman, Joseph
影响因子：
2.8
作者：
Navarro-García, F;Eisman, B;Pla, J
通讯作者：
Pla, J
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
影响因子：
4.9
作者：
Balashov, Sergey V.;Park, Steven;Perlin, David S.
通讯作者：
Perlin, David S.