Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast.
Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast.
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DOI：
10.1371/journal.ppat.1003069
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发表时间：
2012-12
期刊：
影响因子：
6.7
通讯作者：
Brown AJ
中科院分区：
文献类型：
--
作者：
Leach MD;Budge S;Walker L;Munro C;Cowen LE;Brown AJ
热适应在所有生物中都至关重要。在酵母中，热休克反应由热休克转录因子Hsf 1控制。在这里，我们已经整合了无偏见的遗传筛选与定向分子解剖，以证明多个信号级联有助于致病性酵母菌白色念珠菌的热适应。我们发现，分子伴侣热休克蛋白90（HSP 90）相互作用，并下调HSF 1，从而调节短期热适应。从长远来看，热适应依赖于与细胞壁重塑相关的关键MAP激酶信号通路：Hog 1，Mkc 1和Cek 1通路。我们证明，这些途径被差异激活，并显示热休克过程中的串扰。因此，环境温度显著影响C的电阻。白念珠菌细胞对细胞壁应力（Calcofluor白色和刚果红）的敏感性，但对渗透应力（NaCl）的敏感性不高。我们还表明，MAP激酶信号的失活破坏了热适应和细胞壁适应之间的这种串扰。重要的是，Hsp 90协调这种串扰。Hsp 90的遗传和药理学抑制破坏了Hsf 1-Hsp 90调节回路，从而干扰HSP基因调节并降低了C.白念珠菌蛋白毒性应激。热休克蛋白90消耗也影响细胞壁的生物合成，通过削弱其客户端蛋白Mkc 1和Hog 1，以及Cek 1，我们牵连作为一个新的热休克蛋白90客户端在这项研究中的激活。因此，Hsp 90调节经典热休克反应的短期Hsf 1介导的激活，通过Mkc 1-Hog 1-和Cek 1-介导的细胞壁重塑协调这种反应与长期热适应。 白色念珠菌是人类已知的最持久的酵母病原体之一，在其他健康个体中引起频繁的粘膜感染（鹅口疮），并且在免疫功能低下的患者中引起潜在的致命性血流感染。C.白色念珠菌定殖于温血动物并占据热缓冲的小生境。然而，在其进化过程中，这种病原体保留了经典的热休克反应，而其他应激反应已显着分化。我们已经建立了必要的，进化上保守的分子伴侣，热休克蛋白90，协调热适应。热休克蛋白90与热休克转录因子Hsf 1相互作用并调节其活性，从而控制清除蛋白毒性应激损伤蛋白所需的热休克蛋白的表达。此外，热休克蛋白90调节的活动，介导细胞壁重塑和长期适应热休克的关键MAP激酶信号通路。这些因子中的任何一个的丧失都会导致耐热性的显著降低。
Thermal adaptation is essential in all organisms. In yeasts, the heat shock response is commanded by the heat shock transcription factor Hsf1. Here we have integrated unbiased genetic screens with directed molecular dissection to demonstrate that multiple signalling cascades contribute to thermal adaptation in the pathogenic yeast Candida albicans. We show that the molecular chaperone heat shock protein 90 (Hsp90) interacts with and down-regulates Hsf1 thereby modulating short term thermal adaptation. In the longer term, thermal adaptation depends on key MAP kinase signalling pathways that are associated with cell wall remodelling: the Hog1, Mkc1 and Cek1 pathways. We demonstrate that these pathways are differentially activated and display cross talk during heat shock. As a result ambient temperature significantly affects the resistance of C. albicans cells to cell wall stresses (Calcofluor White and Congo Red), but not osmotic stress (NaCl). We also show that the inactivation of MAP kinase signalling disrupts this cross talk between thermal and cell wall adaptation. Critically, Hsp90 coordinates this cross talk. Genetic and pharmacological inhibition of Hsp90 disrupts the Hsf1-Hsp90 regulatory circuit thereby disturbing HSP gene regulation and reducing the resistance of C. albicans to proteotoxic stresses. Hsp90 depletion also affects cell wall biogenesis by impairing the activation of its client proteins Mkc1 and Hog1, as well as Cek1, which we implicate as a new Hsp90 client in this study. Therefore Hsp90 modulates the short term Hsf1-mediated activation of the classic heat shock response, coordinating this response with long term thermal adaptation via Mkc1- Hog1- and Cek1-mediated cell wall remodelling. Candida albicans is one of the most persistent yeast pathogens known to man, causing frequent mucosal infections (thrush) in otherwise healthy individuals, and potentially fatal bloodstream infections in immunocompromised patients. C. albicans colonises warm-blooded animals and occupies thermally buffered niches. Yet during its evolution this pathogen has retained the classic heat shock response whilst other stress responses have diverged significantly. We have established that the essential, evolutionarily conserved molecular chaperone, Hsp90, coordinates thermal adaptation. Hsp90 interacts with and modulates the activity of the heat shock transcription factor, Hsf1, thereby controlling the expression of heat shock proteins required for the clearance of proteins damaged by proteotoxic stresses. In addition, Hsp90 modulates the activities of key MAP kinase signalling pathways that mediate cell wall remodelling and long term adaptation to heat shock. Loss of any of these factors results in a significant reduction in thermotolerance.
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影响因子：
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作者：
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DOI：
10.1073/pnas.88.21.9392
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