Ras1 acts through duplicated Cdc42 and Rac proteins to regulate morphogenesis and pathogenesis in the human fungal pathogen Cryptococcus neoformans.
Ras1 acts through duplicated Cdc42 and Rac proteins to regulate morphogenesis and pathogenesis in the human fungal pathogen Cryptococcus neoformans.
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DOI：
10.1371/journal.pgen.1003687
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Alspaugh JA
中科院分区：
文献类型：
--
作者：
Ballou ER;Kozubowski L;Nichols CB;Alspaugh JA
真核细胞的增殖和形态发生依赖于Rho型GTP酶的协同活性，包括Ras、Cdc 42和Rac。性二态真菌新型隐球菌，它编码旁系同源，所有三个非必需的副本，提供了一个独特的模型，以检查这些保守的蛋白质的相互作用。以前，我们证明了RAS 1介导C。通过作为耐热性和交配的中心调节器来调节neoforms的毒力。我们在这里报告ras 1 Δ突变体在极化生长、胞质分裂和细胞周期进程中积累缺陷。我们证明，ras 1 Δ在耐热性和交配中的缺陷可以在很大程度上解释为四种下游Rho-GTP酶的活性受损：Cdc 42旁系同源物Cdc 42和Cdc 420;以及Rac旁系同源物Rac 1和Rac 2。此外，我们证明了单独的GTcloud类在C中扮演不同的Ras依赖角色。新生儿的形态发生和发病机制。Cdc 42旁系同源物主要控制隔蛋白定位和胞质分裂，而Rac旁系同源物在极化细胞生长中起主要作用。总之，这些重复的相关信号蛋白提供了一个强大的系统，允许微生物在宿主来源的细胞应激的存在下增殖。感染新型隐球菌会导致脑部炎症，如果不治疗是致命的。我们努力了解这种真菌在人体内生长的能力，这使我们找到了一种既适用于其他病原体又适用于人类生物学的细胞生长模型。在早期的工作中，我们研究了一种名为Ras 1的蛋白质，并表明隐球菌使用Ras 1在人体内生存和生长。在这项工作中，我们研究Ras 1和其他两个相关的蛋白质，Cdc 42和Rac之间的连接。我们发现，这三个蛋白质家族以各种组合相互作用，使真菌细胞增殖，保持其适当的细胞形状，并交配，每一个都是隐球菌生命周期的一个重要方面。这些相同的蛋白质已经被其他人证明在人类细胞生长和恶性转化中是重要的。这项工作提供了深入的见解，既可以促进我们对真菌病原体的理解，又可以通过提供一个简单的系统来测试蛋白质功能，帮助我们更好地了解哺乳动物细胞的生长和分化，特别是在人类癌症进展过程中发生的变化。
Proliferation and morphogenesis in eukaryotic cells depend on the concerted activity of Rho-type GTPases, including Ras, Cdc42, and Rac. The sexually dimorphic fungus Cryptococcus neoformans, which encodes paralogous, non-essential copies of all three, provides a unique model in which to examine the interactions of these conserved proteins. Previously, we demonstrated that RAS1 mediates C. neoformans virulence by acting as a central regulator of both thermotolerance and mating. We report here that ras1Δ mutants accumulate defects in polarized growth, cytokinesis, and cell cycle progression. We demonstrate that the ras1Δ defects in thermotolerance and mating can be largely explained by the compromised activity of four downstream Rho-GTPases: the Cdc42 paralogs, Cdc42 and Cdc420; and the Rac paralogs, Rac1 and Rac2. Further, we demonstrate that the separate GTPase classes play distinct Ras-dependent roles in C. neoformans morphogenesis and pathogenesis. Cdc42 paralogs primarily control septin localization and cytokinesis, while Rac paralogs play a primary role in polarized cell growth. Together, these duplicate, related signaling proteins provide a robust system to allow microbial proliferation in the presence of host-derived cell stresses. Infection with the organism Cryptococcus neoformans leads to inflammation of the brain and is lethal if left untreated. Our efforts to understand the ability of this fungus to grow in the human body have lead us to a model for cell growth that is applicable both to other pathogens and to human biology. In earlier work, we examined a protein called Ras1 and showed that Cryptococcus uses Ras1 to survive and grow within the human body. In this work, we examine the connection between Ras1 and two other related proteins, Cdc42 and Rac. We have found that these three protein families interact in various combinations to allow the fungal cell to proliferate, to maintain its proper cell shape, and to mate, each of which is an important aspect of the cryptococcal life cycle. These same proteins have been shown by others to be important in human cell growth and malignant transformation. This work provides insight that will both advance our understanding of fungal pathogens and, by providing a simple system in which to test protein function, aid efforts to better understand mammalian cell growth and differentiation, particularly the changes that occur during human cancer progression.
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影响因子：
3
作者：
Ballou, Elizabeth Ripley;Selvig, Kyla;Narloch, Jessica L.;Nichols, Connie B.;Alspaugh, J. Andrew
通讯作者：
Alspaugh, J. Andrew
影响因子：
10.5
作者：
HOFFMAN, CS;WINSTON, F
通讯作者：
WINSTON, F
影响因子：
4.8
作者：
Gao, Y;Xing, J;Zheng, Y
通讯作者：
Zheng, Y
DOI：
10.1038/nrmicro2711
发表时间：
2011-12-12
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.6
作者：
Chen, CB;Dickman, MB
通讯作者：
Dickman, MB