Glucose sensing network in Candida albicans: a sweet spot for fungal morphogenesis.
Glucose sensing network in Candida albicans: a sweet spot for fungal morphogenesis.
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白色念珠菌中的葡萄糖传感网络：真菌形态发生的最佳点。
DOI：
10.1128/ec.00138-09
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Brown,Victoria
中科院分区：
文献类型：
--
作者：
Sabina,Jeffrey;Brown,Victoria
葡萄糖是大多数细胞所偏好的一种普遍存在的碳源（96），最早由Andreas Marggraf于1747年发现（67）。尽管葡萄糖是地球上含量最丰富的己糖（33），但它在生物系统中往往是一种限制性营养物质(2)；这是一种宝贵的资源，生物体为之激烈竞争。一个优雅的遗传例证是，从细菌到人类的生物体都高度进化了用于检测、获取和利用葡萄糖的传感和信号机制（38,76,80,108）。理解真菌中糖感知的框架始于对酿酒酵母（面包酵母）的研究。这种模式真核生物是一种贪婪的嗜糖生物，它能迅速代谢葡萄糖，产生大量的二氧化碳和乙醇，这一特性在至少4000年的人类文明中得到了完善（104）。由于白色念珠菌对人类健康的巨大影响以及最近开发的用于分析其遗传和生化工具，这种远亲人类病原体已成为真菌遗传学研究的首选生物（4,11,68,91）。自白色念珠菌和酿酒酵母最后一次拥有共同祖先（27,84）以来的2亿年间，遗传漂变结合对不同环境的适应，极大地“重新连接”了糖反应网络的调节回路（12,63,83）。对于白色念珠菌来说，葡萄糖也是一种影响酵母向菌丝转变的形态原（37），这一特性对宿主的最佳毒力至关重要（文献7）。这两种真菌主要通过三种途径感知葡萄糖，这些途径都不是单独运作的（图1）：(i) SRR（糖受体-阻遏物）途径，（ii）葡萄糖抑制途径，（iii）腺苷酸环化酶途径。每个系统都利用不同的信号转导级联，但广泛的交叉调节将它们编织成一个单一的糖反应网络。SRR途径。己糖转运蛋白是12种跨膜跨越蛋白，在质膜上形成底物选择孔，促进真核细胞摄取葡萄糖（42,53）。转运蛋白是一个非常大的蛋白质家族的一部分，称为主要促进剂超家族，其成员通过促进分子的扩散（不要与同运或反运混淆）运输溶质（28,42,98,108）。它们由大的基因家族（多达17个成员）编码，并且可以包含物种特异性的蛋白质特征，使它们成为真核病原体的新药物靶点（31）。在真菌中，大己糖转运体家族的一些成员已经进化成葡萄糖和其他结构相关的己糖的传感器。cerevisiae在质膜中使用高亲和力（Snf3）和低亲和力（Rgt2）葡萄糖传感器来监测环境中的葡萄糖水平（70）。虽然尚未证实与己糖的直接结合，但Snf3和Rgt2几乎肯定是葡萄糖受体，因为它们在整个糖结合域与己糖转运体高度相似，并且它们对细胞对葡萄糖的反应至关重要（70）。这种类型的传感器无法输入葡萄糖，从功能性转运蛋白（即人类GLUT1或酵母Hxt/Hgt蛋白）的研究中可以获得的见解尚未解决传感器无法运输的分子基础（22,43,44,77）。相反，传感器产生细胞内信号，诱导适当的己糖转运蛋白（HXT）基因的表达。每个传感器都有一个c端细胞质尾部（在转运体中不存在），它既不是信号产生的必要条件，也不是充分条件，也不会物理阻塞运输（65）。因此，人们认为……
Glucose, a ubiquitous carbon source preferred by most cells (96), was first identified by Andreas Marggraf in 1747 (67). Even though it is the most abundant hexose on earth (33), glucose is often a limiting nutrient in biological systems (2); it is a precious resource for which organisms fiercely compete (54). An elegant genetic illustration of this is the fact that organisms from bacteria to humans have highly evolved sensing and signaling machinery dedicated to the detection, acquisition, and utilization of glucose (38, 76, 80, 108). The framework for understanding sugar sensing in fungi began with studies of Saccharomyces cerevisiae (baker’s yeast). This model eukaryote is a voracious glucophile that rapidly metabolizes glucose to produce massive amounts of CO2 and ethanol, a trait refined over at least 4,000 years of human civilization (104). The distantly related human pathogen Candida albicans has become an organism of choice for fungal genetics, motivated by its huge impact on human health and thanks to recently developed genetic and biochemical tools for its analysis (4, 11, 68, 91). In the 200 million years since C. albicans and S. cerevisiae last shared a common ancestor (27, 84), genetic drift combined with adaptation to differing environments has drastically “rewired” the regulatory circuitry of the sugar response network (12, 63, 83). For C. albicans, glucose is also a morphogen that inffuences yeast-to-hypha transitions (37), and this trait is critical for optimal virulence in the host (reviewed in reference 7). Both fungi sense glucose mainly through three pathways, none of which operates in isolation (Fig. 1):(i) the SRR (sugar receptor-repressor) pathway,(ii) the glucose repression pathway, and (iii) the adenylate cyclase pathway. Each system utilizes a distinct signal transduction cascade, but extensive cross-regulation weaves them together into a single sugar response network. SRR pathway. Hexose transporters, which are 12 transmembrane-spanning proteins that form substrate-selective pores in the plasma membrane, facilitate glucose uptake into eukaryotic cells (42, 53). The transporters are part of a very large protein family called the major facilitator superfamily whose members transport solutes by facilitated diffusion (not to be confused with symporting or antiporting) of molecules (28, 42, 98, 108). They are encoded by large gene families (up to 17 members) and can harbor species-specific protein signatures that make them novel drug targets in eukaryotic pathogens (31). In fungi, select members of the large hexose transporter family have evolved into sensors of glucose and other structurally related hexoses.S. cerevisiae employs both a high-affinity (Snf3) and a lowaffinity (Rgt2) glucose sensor poised in the plasma membrane to monitor glucose levels in the environment (70). Although direct binding to hexoses has not been demonstrated, Snf3 and Rgt2 are almost certainly glucose receptors because they are highly similar to hexose transporters throughout their sugarbinding domains, and they are critical for the cell’s response to glucose (70). Sensors of this type are incapable of importing glucose, and what insight can be gleaned from work on functional transporters (ie, human GLUT1 or yeast Hxt/Hgt proteins) does not yet resolve the molecular basis underlying a sensors’ inability to transport (22, 43, 44, 77). Instead, sensors generate an intracellular signal that induces the expression of appropriate hexose transporter (HXT) genes. Each sensor has a C-terminal cytoplasmic tail (absent from transporters) that is neither necessary nor sufficient for signal generation and that does not physically occlude transport (65). Therefore, it is believed …
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