Mechanisms of regulation of ribosome biogenesis and stress resistance in yeast

在真核细胞中，近三分之一的新合成蛋白质进入内质网（ER），这是一种包含特殊质量控制机制的细胞器，可确保新生肽的适当折叠。如果不能折叠成正确的构象，就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通路，以响应由突变或环境损害等各种因素引起的内质网错误折叠蛋白负荷（内质网应激）的突然增加。在内质网应激下，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内质网稳态。利用出芽酵母酿酒酵母（Saccharomyces cerevisiae）对内质网应激解决机制和UPR进行了广泛的研究，从而实现了快速和广泛的遗传操作。酵母还拥有一个更简单的后生动物UPR版本，使我们能够破译基本机制。

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 mutation 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. 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. Yeast also possess a much simpler version of the metazoan UPR, allowing us to decipher basic mechanisms.  Interestingly, ER stress activates other pathways beyond the UPR. In yeast, prolonged ER stress prevents delivery of properly folded proteins to the cell wall, activating another coping mechanism, the cell wall integrity pathway (CWI). During ER stress, distinct branches of the CWI pathway have two major roles: to increase synthesis of cell wall components to repair defects and to repress ribosome biogenesis. Dividing yeast cells allocate much of their resources to ribosome biogenesis, thus, repression of ribosome production is essential to reallocate resources to stress response pathways such as the CWI and the UPR. However, new data from my laboratory indicate that, while beneficial for acute ER stress, prolonged repression of ribosome biogenesis is detrimental to cells and prevents their re-entry into the growth phase upon resolution of ER stress. My central hypothesis is that increased synthesis of cell wall components during chronic ER stress will attenuate the repression of ribosome biogenesis, allow protein synthesis, and ultimately increase cell survival. The long-term goal of my research program is to understand how the CWI pathway links ER stress tolerance to ribosome biogenesis and cell growth. Specifically, my short-term objectives are to: (1) Elucidate how CWI regulates cellular responses to ER stress. (2) Define how CWI regulates ribosome biogenesis during prolonged ER stress. (3) Identify the genetic networks controlling CWI-dependent tolerance to ER stress. This program will uncover new, fundamental regulatory mechanisms for adaptation to ER stress that are independent of UPR activation and could later be investigated in other systems.