Regulation of endoplasmic reticulum stress resistance in yeast

酵母内质网应激抵抗的调控

• 批准号: RGPIN-2022-05267
• 负责人: Lajoie, Patrick
• 金额: $ 2.33万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=743449
• 关键词: Regulation; endoplasmic; reticulum; stress; resistance

In eukaryotic cells, nearly one third of all newly synthetized proteins enter the endoplasmic reticulum (ER), an organelle containing specialized quality control machinery that ensures the proper folding of the nascent peptides. Failure to fold into their proper conformation leads to loss of protein function and cell death. Thus, cells have evolved signaling pathways that respond to sudden increases in the ER misfolded protein burden (ER stress) caused by various factors such as genetic mutations or environmental insults. In response to ER stress, cells activate the unfolded protein response (UPR). This evolutionarily conserved coping mechanism increases the expression of genes encoding proteins that help restore ER homeostasis by improving protein folding and misfolded protein degradation. Recently, it has emerged that the UPR can not only be activated by misfolded proteins, but also by changes in the lipid composition of the ER membrane. The biological relevance of this differential activation remains elusive. The mechanisms of ER stress resolution and UPR have been extensively characterized using the budding yeast Saccharomyces cerevisiae, which allows rapid and extensive genetic manipulations. However, the role of the UPR is other yeast species such as the pathogen Candida albicans remains poorly understood. Interestingly, C. albicans cells with compromised UPR display hypersensitivity to antifungal drugs and reduced pathogenicity. Using a combination of studies in both S. cerevisiae and C. albicans, I propose to investigate how the UPR control gene expression associated with the antifungal response and pathogenicity. My central hypothesis is that the different mode of UPR activation deploys a specific transcriptional program that adapt the ER folding environment to regulate antifungal resistance and pathogenicity. The long-term goal of my research program is to identify the underlying mechanisms that control UPR-driven antifungal resistance and pathogenicity. Specifically, my short-term objectives are to: (1) Elucidate how the ER stress sensor Ire1 is activated by antifungal drugs. (2) Define the C. albicans UPR. (3) Characterize the role of UPR target genes in C. albicans antifungal resistance and pathogenicity This program will uncover new, fundamental regulatory mechanisms for antifungal resistance that can later be investigated in various other microbial organisms. Our study will contribute to establish new approaches to prevent evolution of pathogen resistance to antifungals.

在真核细胞中，近三分之一的新合成蛋白质进入内质网（ER），内质网是一种含有专门的质量控制机制的细胞器，可确保新生肽的正确折叠。不能折叠成正确的构象会导致蛋白质功能丧失和细胞死亡。因此，细胞已经进化出信号传导途径，这些信号传导途径响应于由各种因素如基因突变或环境损伤引起的ER错误折叠蛋白质负荷（ER应激）的突然增加。为了响应ER应激，细胞激活未折叠蛋白反应（UPR）。这种进化上保守的应对机制增加了编码蛋白质的基因的表达，这些蛋白质通过改善蛋白质折叠和错误折叠的蛋白质降解来帮助恢复ER稳态。最近，它已经出现，UPR不仅可以激活错误折叠的蛋白质，但也通过改变ER膜的脂质组成。这种差异激活的生物学相关性仍然难以捉摸。ER应力决议和UPR的机制已被广泛使用的芽殖酵母酿酒酵母，它允许快速和广泛的遗传操作的特点。然而，UPR的作用是其他酵母物种，如病原体白色念珠菌仍然知之甚少。有趣的是，C。UPR受损的白念珠菌细胞显示对抗真菌药物的超敏反应和降低的致病性。结合S.酿酒酵母和C.因此，本研究拟探讨UPR调控基因表达与抗真菌反应及致病性的关系。 我的中心假设是，UPR激活的不同模式部署了一个特定的转录程序，适应ER折叠环境，以调节抗真菌药物的耐药性和致病性。我的研究计划的长期目标是确定控制UPR驱动的抗真菌药物耐药性和致病性的潜在机制。 具体而言，我的短期目标是：（1）阐明ER应激传感器Ire 1如何被抗真菌药物激活。 (2)定义C。白色念珠菌UPR。 (3)探讨UPR靶基因在C.白念珠菌抗真菌耐药性和致病性该计划将揭示新的，基本的抗真菌耐药性的调节机制，以后可以在各种其他微生物中进行研究。我们的研究将有助于建立新的方法来防止病原体对抗真菌药物的耐药性的演变。