Specialization of the HOG pathway and its impact on differentiation and virulence of Cryptococcus neoformans
Specialization of the HOG pathway and its impact on differentiation and virulence of Cryptococcus neoformans
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DOI：
10.1091/mbc.e04-11-0987
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发表时间：
2005-05-01
影响因子：
3.3
通讯作者：
Heitman, J
中科院分区：
文献类型：
--
作者：
Bahn, YS;Kojima, K;Heitman, J
在过去的1000万到4000万年里，人类致病真菌新隐球菌已经从一个共同的祖先分化成三个生物学上截然不同的品种或兄弟物种。在这些不同形式的进化过程中，血清型甲型新生格鲁比变种已成为最具毒性和世界性致病性的分支。因此，了解血清型新生甲型C.如何与不太成功的致病血清型区分开来，将为真菌毒力的进化提供见解。在这里，我们报告了结构保守的Pbs2-Hog1 MAP激酶级联蛋白被特异性募集为一种全局调节剂，以控制高毒力的a型H99临床分离株的形态分化和毒力因子，但在实验室生成的弱毒的D型菌株JEC21中却没有。两种菌株对Hog1的调控机制存在显著差异，且与JEC21等酵母相比，Hog1在H99中的磷酸化动力学和定位模式完全相反。在H99临床分离株中观察到的独特的Hog1调控模式广泛存在于A血清型菌株中，也存在于一些D血清型临床分离株中。血清型A hog1 Delta和pbs2 Delta突变体的毒力减弱，进一步强调了pbs2 - hog1 MAPK级联在隐球菌病发病机制中的作用。
The human pathogenic fungus Cryptococcus neoformans has diverged from a common ancestor into three biologically distinct varieties or sibling species over the past 10-40 million years. During evolution of these divergent forms, serotype A C. neoformans var. grubii has emerged as the most virulent and cosmopolitan pathogenic clade. Therefore, understanding how serotype A C. neoformans is distinguished from less successful pathogenic serotypes will provide insights into the evolution of fungal virulence. Here we report that the structurally conserved Pbs2-Hog1 MAP kinase cascade has been specifically recruited as a global regulator to control morphological differentiation and virulence factors in the highly virulent serotype A H99 clinical isolate, but not in the laboratory-generated and less virulent serotype D strain JEC21. The mechanisms of Hog1 regulation are strikingly different between the two strains, and the phosphorylation kinetics and localization pattern of Hogl are opposite in H99 compared with JEC21 and other yeasts. The unique Hog1 regulatory pattern observed in the H99 clinical isolate is widespread in serotype A strains and is also present in some clinical serotype D isolates. Serotype A hog1 Delta and pbs2 Delta mutants are attenuated in virulence, further underscoring the role of the Pbs2-Hog1 MAPK cascade in the pathogenesis of cryptococcosis.