A unique cell wall synthetic response evoked by glucosamine determines pathogenicity-associated fungal cellular differentiation.
A unique cell wall synthetic response evoked by glucosamine determines pathogenicity-associated fungal cellular differentiation.
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葡萄糖胺引起的独特细胞壁合成反应决定了致病性相关的真菌细胞分化
DOI：
10.1371/journal.pgen.1009817
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发表时间：
2021-10
期刊：
影响因子：
4.5
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Hu P;Ding H;Shen L;He GJ;Liu H;Tian X;Tao C;Bai X;Liang J;Jin C;Xu X;Yang E;Wang L
酵母到菌丝的转变与许多人类致病真菌的致病性密切相关，例如模式真菌病原体新型隐球菌，每年造成约18万人死亡。在这种病原体中，酵母到菌丝的转变可以由不同的刺激启动：交配刺激或葡萄糖胺（GlcN），细胞壁壳聚糖的单体。然而，它仍然知之甚少的信号特异性隐球菌形态转变的不同刺激是如何确保。在这里，通过整合时间表达特征分析和基于现象的聚类评估，我们证明了GlcN特异性地触发了一种独特的细胞反应，这是GlcN诱导的丝化（GIF）激活的关键决定因素。这种细胞反应被定义为异常活跃的细胞壁合成，高度消耗atp。一个新的细胞表面蛋白Gis1被鉴定为glcn诱导的细胞壁反应的指示分子。mpk1导向的细胞壁通路在细胞壁基因诱导和细胞内ATP供应之间起着关键的桥梁作用，确保了gis1依赖性的细胞壁反应和GIF的刺激特异性。我们进一步发现Mpk1协调细胞壁反应和GIF激活的能力在不同的隐球菌病原体中是保守的。基于磷酸化蛋白组学的分析以及遗传和表型分析表明，Mpk1激酶通过以Skn7和Crz1为中心的协调下游调控网络介导GIF的调控特异性。总的来说，我们的研究发现了一个前所未有的、保守的细胞壁生物合成依赖的真菌分化承诺机制，这使得GlcN在隐球菌病原体中诱导的致病性相关二态性的信号特异性成为可能。
The yeast-to-hypha transition is tightly associated with pathogenicity in many human pathogenic fungi, such as the model fungal pathogen Cryptococcus neoformans, which is responsible for approximately 180,000 deaths annually. In this pathogen, the yeast-to-hypha transition can be initiated by distinct stimuli: mating stimulation or glucosamine (GlcN), the monomer of cell wall chitosan. However, it remains poorly understood how the signal specificity for Cryptococcus morphological transition by disparate stimuli is ensured. Here, by integrating temporal expression signature analysis and phenome-based clustering evaluation, we demonstrate that GlcN specifically triggers a unique cellular response, which acts as a critical determinant underlying the activation of GlcN-induced filamentation (GIF). This cellular response is defined by an unusually hyperactive cell wall synthesis that is highly ATP-consuming. A novel cell surface protein Gis1 was identified as the indicator molecule for the GlcN-induced cell wall response. The Mpk1-directed cell wall pathway critically bridges global cell wall gene induction and intracellular ATP supply, ensuring the Gis1-dependent cell wall response and the stimulus specificity of GIF. We further reveal that the ability of Mpk1 to coordinate the cell wall response and GIF activation is conserved in different Cryptococcus pathogens. Phosphoproteomics-based profiling together with genetic and phenotypic analysis revealed that the Mpk1 kinase mediates the regulatory specificity of GIF through a coordinated downstream regulatory network centered on Skn7 and Crz1. Overall, our findings discover an unprecedented and conserved cell wall biosynthesis-dependent fungal differentiation commitment mechanism, which enables the signal specificity of pathogenicity-related dimorphism induced by GlcN in Cryptococcus pathogens.
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