Control of the C. albicans cell wall damage response by transcriptional regulator Cas5.
Control of the C. albicans cell wall damage response by transcriptional regulator Cas5.
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DOI：
10.1371/journal.ppat.0020021
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发表时间：
2006-03
期刊：
影响因子：
6.7
通讯作者：
Mitchell, Aaron P
中科院分区：
文献类型：
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作者：
Bruno, Vincent M;Kalachikov, Sergey;Subaran, Ryan;Nobile, Clarissa J;Kyratsous, Christos;Mitchell, Aaron P
真菌细胞壁对细胞的生长、发育和细胞与环境的相互作用至关重要。对出芽酵母酿酒酵母（Saccharomyces cerevisiae）的研究很好地理解了细胞壁损伤的反应，其中许多细胞壁完整性（CWI）基因被转录因子ScRlm1激活。先前的证据表明，在主要的真菌病原体白色念珠菌中，反应和调节可能都是保守的。我们利用一种新的白色念珠菌遗传资源验证了这一假设：我们筛选了对细胞壁生物合成抑制剂caspofungin敏感的推定转录因子基因缺陷突变体。我们发现锌指蛋白CaCas5控制着许多CWI基因的表达，而该蛋白在酿酒酵母中缺乏独特的同源物。carm1在这一反应中起着适度的作用。转录辅激活因子CaAda2也是许多CaCas5依赖基因表达所必需的，正如预期的那样，如果CaCas5招募CaAda2来激活靶基因转录。许多caspfunin诱导的白色念珠菌基因指定内质网和分泌功能。这些基因在酿酒葡萄球菌中不被诱导，但在caspofungin中促进其生长。我们利用新的资源鉴定了一个关键的白色念珠菌CWI基因转录调控因子和抗真菌敏感性。我们的基因表达结果表明，发散性和保守性反应基因都可能具有重要的功能作用。我们的策略可能广泛用于鉴定病原体特异性调控途径和关键反应基因。对于微生物病原体来说，细胞壁是与宿主和环境相互作用的关键。白色念珠菌是主要的真菌病原体，它的细胞壁与酿酒酵母菌的细胞壁相似，我们对白色念珠菌细胞壁的生物发生和修复的了解大多来自酿酒酵母菌的外推。在这里，Bruno和他的同事们使用一种新开发的白色念珠菌遗传策略，直接探讨了白色念珠菌对抗真菌药物caspofungin破坏细胞壁生物发生的反应机制。他们发现这种反应本身与酿酒葡萄球菌有许多相似之处，但调控回路是不同的：白色念珠菌的主要调控基因在酿酒葡萄球菌的基因中没有明确的对应基因。他们的发现提供了一个独特的白色念珠菌调节功能的新例子，并且可能在识别新药和了解可能的耐药机制方面证明是有用的。
The fungal cell wall is vital for growth, development, and interaction of cells with their environment. The response to cell wall damage is well understood from studies in the budding yeast Saccharomyces cerevisiae, where numerous cell wall integrity (CWI) genes are activated by transcription factor ScRlm1. Prior evidence suggests the hypothesis that both response and regulation may be conserved in the major fungal pathogen Candida albicans. We have tested this hypothesis by using a new C. albicans genetic resource: we have screened mutants defective in putative transcription factor genes for sensitivity to the cell wall biosynthesis inhibitor caspofungin. We find that the zinc finger protein CaCas5, which lacks a unique ortholog in S. cerevisiae, governs expression of many CWI genes. CaRlm1 has a modest role in this response. The transcriptional coactivator CaAda2 is also required for expression of many CaCas5-dependent genes, as expected if CaCas5 recruits CaAda2 to activate target gene transcription. Many caspofungin-induced C. albicans genes specify endoplasmic reticulum and secretion functions. Such genes are not induced in S. cerevisiae, but promote its growth in caspofungin. We have used a new resource to identify a key C. albicans transcriptional regulator of CWI genes and antifungal sensitivity. Our gene expression findings indicate that both divergent and conserved response genes may have significant functional roles. Our strategy may be broadly useful for identification of pathogen-specific regulatory pathways and critical response genes. For microbial pathogens, the cell wall is critical for interaction with both host and environment. The major fungal pathogen, Candida albicans, has a cell wall that resembles that of the model yeast Saccharomyces cerevisiae, and much of what is known about C. albicans cell wall biogenesis and repair comes via extrapolation from S. cerevisiae. Here, Bruno and colleagues inquired directly into the mechanisms that C. albicans uses to respond to disruption of cell wall biogenesis by the antifungal drug caspofungin, using a genetic strategy newly developed for C. albicans. They found that the response itself has many similarities to that of S. cerevisiae, but the regulatory circuitry is distinct: the major C. albicans regulatory gene has no clear counterpart among S. cerevisiae genes. Their findings provide a new example of a unique C. albicans regulatory function and one that may prove useful in identifying new drugs and in understanding possible resistance mechanisms.