Translational control mechanisms in Candida albicans: Exploring the link between RNA helicases and pathogenicity determinants

白色念珠菌是大多数健康人体内正常微生物菌群的一部分，但它也可以成为一种病原体，在宿主防御受损时引起表面和危及生命的侵入性感染。白色念珠菌的定植和感染几乎所有身体部位的能力依赖于它对不同宿主生态位所遇到的不断变化的环境条件的成功适应，其中包括基因表达的适当调整。过去几十年的研究为白色念珠菌的转录控制机制提供了详细的见解。许多调节形态发生、代谢适应和抗真菌药物反应的信号通路和转录因子已经被发现，转录物丰度的相应变化已经在全基因组范围内被确定。然而，基因也在转录后水平受到调控，令人惊讶的是，人们对白色念珠菌基因表达的翻译控制知之甚少。在这个印德合作研究项目中，我们使用最先进的技术和我们互补的专业知识来阐明白色念珠菌基因组水平上基因表达的翻译调控和这种控制的机制。我们将确定哪些基因能够使代谢适应营养可用性，从出芽酵母到侵入性菌丝形态的转变，以及抗真菌药物耐药性的发展受到翻译调节。我们将揭示mrna的哪些特征是翻译控制所必需的，并研究DEAD-box RNA解旋酶eIF4A（真核起始因子4A）和Ded1的作用，这些酶迄今尚未在白色念珠菌中被表征。我们将研究缺乏这些解旋酶的突变体的表型，以及它们的失活对整体翻译控制的影响，以及对在菌丝形态发生、代谢适应和耐药性中具有关键功能的特定基因的翻译效率的影响。我们的研究结果将扩大我们对医学上最重要的真菌之一如何适应其人类宿主的生活并成为致病性的理解，并且它们也将揭示真核生物翻译控制机制的保存和分歧。

The yeast Candida albicans is part of the normal microbial flora in most healthy people, but it can also become a pathogen and cause superficial as well as life-threatening invasive infections when host defences are compromised. The ability of C. albicans to colonize and infect virtually all body locations relies on its successful adaptation to the changing environmental conditions encountered in different host niches, which includes appropriate adjustments in gene expression. Research over the past decades has provided detailed insights into transcriptional control mechanisms in C. albicans. Many signaling pathways and transcription factors that regulate morphogenesis, metabolic adaptations, and the response to the presence of antifungal drugs have been uncovered, and the corresponding changes in transcript abundance have been determined on a genome-wide scale. However, genes are also regulated at the posttranscriptional level, and surprisingly little is known about translational control of gene expression in C. albicans. In this collaborative Indo-German research project we use state-of-the art techniques and our complementary expertises to elucidate the translational regulation of gene expression in C. albicans on a genome-wide level and the mechanisms of this control. We will determine which of the genes that enable metabolic adaptations to nutrient availability, the transition from the budding yeast to the invasive hyphal morphology, and the development of antifungal drug resistance are translationally regulated. We will reveal which features of mRNAs are required for translational control and investigate the role of the DEAD-box RNA helicases eIF4A (eukaryotic initiation factor 4A) and Ded1, which have not been characterized so far in C. albicans. We will study the phenotypes of mutants lacking these helicases and the effect of their inactivation on global translational control as well as on the translational efficiency of specific genes with key functions in hyphal morphogenesis, metabolic adaptation, and drug resistance. The results of our studies will expand our understanding of how one of the medically most important fungi adapts to life in its human host and can become pathogenic, and they will also reveal conservation and divergence of translational control mechanisms in eukaryotes.