The evolutionary rewiring of ubiquitination targets has reprogrammed the regulation of carbon assimilation in the pathogenic yeast Candida albicans.
The evolutionary rewiring of ubiquitination targets has reprogrammed the regulation of carbon assimilation in the pathogenic yeast Candida albicans.
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DOI：
10.1128/mbio.00495-12
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发表时间：
2012-12-11
期刊：
影响因子：
6.4
通讯作者：
Brown AJ
中科院分区：
文献类型：
--
作者：
Sandai D;Yin Z;Selway L;Stead D;Walker J;Leach MD;Bohovych I;Ene IV;Kastora S;Budge S;Munro CA;Odds FC;Gow NA;Brown AJ
微生物必须吸收碳才能生长并定居在它们的生态位上。转录谱分析表明，白色念珠菌，人类的主要病原体，调节其碳同化的模式酵母酿酒酵母，抑制代谢途径所需的替代非首选的碳源时，糖是可用的。然而，我们发现在白色念珠菌中蛋白质组和转录组之间存在显著的错位。葡萄糖触发白色念珠菌中ICL 1和PCK 1转录物的降解，但异柠檬酸裂解酶（Icl 1）和磷酸烯醇丙酮酸羧激酶（Pck 1）是稳定的并被保留。事实上，羧酸和脂肪酸同化所需的许多酶不会响应于葡萄糖而降解。然而，当在白色念珠菌中表达时，S.酿酒酵母Icl 1（ScIcl 1）经历葡萄糖加速降解，表明与酿酒酵母一样，该病原体具有执行泛素依赖性分解代谢物失活所需的分子装置。白色念珠菌Icl 1（CaIcl 1）缺乏类似的泛素化位点，在这些条件下是稳定的，但添加一个泛素化位点程序葡萄糖加速CaIcl 1的降解。此外，在白色念珠菌ubi4细胞中，分解代谢物失活减慢。泛素化位点存在于来自酿酒酵母的产纤维素酶和乙醛酸循环酶中，但不存在于它们的白色念珠菌同源物中。我们的结论是，泛素化靶点的进化重新布线意味着在葡萄糖暴露后，白色念珠菌保留了关键的代谢功能，使其能够继续同化替代碳源。这种代谢灵活性在感染期间可能至关重要，有助于快速定殖含有复杂营养物质的动态宿主生态位。病原微生物必须吸收一系列碳源才能生长并定殖其宿主。目前关于致病性酵母白色念珠菌中碳同化的观点受到酿酒酵母范例的强烈影响，在酿酒酵母范例中，面临营养选择的细胞首先使用能量有利的糖，降解同化不太有利的替代碳源所需的酶。我们表明，这是不是在白色念珠菌的情况下，因为有显着的进化重新布线的分子信号，促进酶降解葡萄糖的反应。因此，人类的这种主要病原体保留了利用生理相关碳源（如乳酸和脂肪酸）所需的酶，使其即使在葡萄糖可用时也能继续利用这些宿主营养素。这种现象可能会提高宿主生态位的有效殖民地，糖只是短暂的。
Microbes must assimilate carbon to grow and colonize their niches. Transcript profiling has suggested that Candida albicans, a major pathogen of humans, regulates its carbon assimilation in an analogous fashion to the model yeast Saccharomyces cerevisiae, repressing metabolic pathways required for the use of alterative nonpreferred carbon sources when sugars are available. However, we show that there is significant dislocation between the proteome and transcriptome in C. albicans. Glucose triggers the degradation of the ICL1 and PCK1 transcripts in C. albicans, yet isocitrate lyase (Icl1) and phosphoenolpyruvate carboxykinase (Pck1) are stable and are retained. Indeed, numerous enzymes required for the assimilation of carboxylic and fatty acids are not degraded in response to glucose. However, when expressed in C. albicans, S. cerevisiae Icl1 (ScIcl1) is subjected to glucose-accelerated degradation, indicating that like S. cerevisiae, this pathogen has the molecular apparatus required to execute ubiquitin-dependent catabolite inactivation. C. albicans Icl1 (CaIcl1) lacks analogous ubiquitination sites and is stable under these conditions, but the addition of a ubiquitination site programs glucose-accelerated degradation of CaIcl1. Also, catabolite inactivation is slowed in C. albicans ubi4 cells. Ubiquitination sites are present in gluconeogenic and glyoxylate cycle enzymes from S. cerevisiae but absent from their C. albicans homologues. We conclude that evolutionary rewiring of ubiquitination targets has meant that following glucose exposure, C. albicans retains key metabolic functions, allowing it to continue to assimilate alternative carbon sources. This metabolic flexibility may be critical during infection, facilitating the rapid colonization of dynamic host niches containing complex arrays of nutrients. Pathogenic microbes must assimilate a range of carbon sources to grow and colonize their hosts. Current views about carbon assimilation in the pathogenic yeast Candida albicans are strongly influenced by the Saccharomyces cerevisiae paradigm in which cells faced with choices of nutrients first use energetically favorable sugars, degrading enzymes required for the assimilation of less favorable alternative carbon sources. We show that this is not the case in C. albicans because there has been significant evolutionary rewiring of the molecular signals that promote enzyme degradation in response to glucose. As a result, this major pathogen of humans retains enzymes required for the utilization of physiologically relevant carbon sources such as lactic acid and fatty acids, allowing it to continue to use these host nutrients even when glucose is available. This phenomenon probably enhances efficient colonization of host niches where sugars are only transiently available.