Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
PLoS Genet. 2020 Jan 21;16(1):e1008582. doi: 10.1371/journal.pgen.1008582. eCollection 2020 Jan.
Metabolic adaptation is linked to the ability of the opportunistic pathogen Candida albicans to colonize and cause infection in diverse host tissues. One way that C. albicans controls its metabolism is through the glucose repression pathway, where expression of alternative carbon source utilization genes is repressed in the presence of its preferred carbon source, glucose. Here we carry out genetic and gene expression studies that identify transcription factors Mig1 and Mig2 as mediators of glucose repression in C. albicans. The well-studied Mig1/2 orthologs ScMig1/2 mediate glucose repression in the yeast Saccharomyces cerevisiae; our data argue that C. albicans Mig1/2 function similarly as repressors of alternative carbon source utilization genes. However, Mig1/2 functions have several distinctive features in C. albicans. First, Mig1 and Mig2 have more co-equal roles in gene regulation than their S. cerevisiae orthologs. Second, Mig1 is regulated at the level of protein accumulation, more akin to ScMig2 than ScMig1. Third, Mig1 and Mig2 are together required for a unique aspect of C. albicans biology, the expression of several pathogenicity traits. Such Mig1/2-dependent traits include the abilities to form hyphae and biofilm, tolerance of cell wall inhibitors, and ability to damage macrophage-like cells and human endothelial cells. Finally, Mig1 is required for a puzzling feature of C. albicans biology that is not shared with S. cerevisiae: the essentiality of the Snf1 protein kinase, a central eukaryotic carbon metabolism regulator. Our results integrate Mig1 and Mig2 into the C. albicans glucose repression pathway and illuminate connections among carbon control, pathogenicity, and Snf1 essentiality.
代谢适应与机会性病原体白念珠菌定植和感染不同宿主组织的能力有关。白念珠菌控制其代谢的一种方式是通过葡萄糖抑制途径，即在其首选碳源葡萄糖存在的情况下，抑制替代碳源利用基因的表达。在这里，我们进行了遗传和基因表达研究，确定转录因子 Mig1 和 Mig2 是白念珠菌葡萄糖抑制的介质。经过充分研究的 Mig1/2 同源物 ScMig1/2 在酵母酿酒酵母中介导葡萄糖抑制；我们的数据表明，白念珠菌 Mig1/2 作为替代碳源利用基因的抑制剂发挥类似的作用。然而，Mig1/2 在白念珠菌中的功能具有几个独特的特征。首先，Mig1 和 Mig2 在基因调控中具有更平等的作用，而不是它们的酿酒酵母同源物。其次，Mig1 在蛋白质积累水平上受到调节，更类似于 ScMig2 而不是 ScMig1。第三，Mig1 和 Mig2 共同需要白念珠菌生物学的一个独特方面，即表达几种致病性特征。这种 Mig1/2 依赖性特征包括形成菌丝和生物膜的能力、细胞壁抑制剂的耐受性以及损伤巨噬细胞样细胞和人内皮细胞的能力。最后，Mig1 是白念珠菌生物学中一个令人困惑的特征所必需的，而这一特征与酿酒酵母不同：Snf1 蛋白激酶的必需性，Snf1 是一种中央真核碳代谢调节剂。我们的研究结果将 Mig1 和 Mig2 整合到白念珠菌葡萄糖抑制途径中，并阐明了碳控制、致病性和 Snf1 必要性之间的联系。
