Retigeric acid B attenuates the virulence of Candida albicans via inhibiting adenylyl cyclase activity targeted by enhanced farnesol production.
Retigeric acid B attenuates the virulence of Candida albicans via inhibiting adenylyl cyclase activity targeted by enhanced farnesol production.
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DOI：
10.1371/journal.pone.0041624
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lou H
中科院分区：
文献类型：
--
作者：
Chang W;Li Y;Zhang L;Cheng A;Lou H
白色念珠菌是最常见的真菌病原体，它经历了酵母到菌丝的转换，这一直被认为是真菌毒力的关键因素。我们在这里发现，地衣衍生的小分子滤光酸B （RAB）作为一种抑制剂，可以显著抑制白色念珠菌的丝化，从而延长感染白色念珠菌的线虫的存活时间。实时荧光定量PCR分析和细胞内cAMP测定显示，RAB通过降低cAMP水平调控Ras1-cAMP-Efg1通路，抑制菌丝形成。共聚焦显微镜观察显示，RAB诱导Dpp3的表达，合成了更多的法尼醇，经气相色谱-质谱检测证实。腺苷酸环化酶活性测定表明，RAB可以通过刺激法尼醇合成来抑制Cdc35的活性，从而导致cAMP合成减少，导致酵母向菌丝过渡的延迟。此外，细胞内cAMP水平的降低导致下游粘附素的抑制。总之，这些发现表明，RAB刺激法尼醇的产生，直接抑制Cdc35活性，减少cAMP的合成，从而导致白色念珠菌形态转变的破坏和减弱毒力。我们的工作阐明了rab依赖性抑制酵母-菌丝转换的潜在机制，并为治疗白色念珠菌感染提供了潜在的应用。
Candida albicans, the most prevalent fungal pathogen, undergoes yeast-to-hyphal switch which has long been identified as a key fungal virulence factor. We showed here that the lichen-derived small molecule retigeric acid B (RAB) acted as an inhibitor that significantly inhibited the filamentation of C. albicans, leading to the prolonged survival of nematodes infected by C. albicans. Quantitative real-time PCR analysis and intracellular cAMP measurement revealed RAB regulated the Ras1-cAMP-Efg1 pathway by reducing cAMP level to inhibit the hyphae formation. Confocal microscopic observation showed RAB induced the expression of Dpp3, synthesizing more farnesol, which was confirmed by gas chromatography-mass spectroscopy detection. An adenylyl cyclase activity assay demonstrated RAB could repress the activity of Cdc35 through stimulating farnesol synthesis, thus causing a decrease in cAMP synthesis, leading to retarded yeast-to-hyphal transition. Moreover, reduced levels of intracellular cAMP resulted in the inhibition of downstream adhesins. Together, these findings indicate that RAB stimulates farnesol production that directly inhibits the Cdc35 activity, reducing the synthesis of cAMP and thereby causing the disruption of the morphologic transition and attenuating the virulence of C. albicans. Our work illustrates the underlying mechanism of RAB-dependent inhibition of the yeast-to-hyphal switch and provides a potential application in treating the infection of C. albicans.
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影响因子：
2.6
作者：
Gerami-Nejad, M;Berman, J;Gale, CA
通讯作者：
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影响因子：
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作者：
Enjalbert, B;Whiteway, M
通讯作者：
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