Engineering a Model Cell for Rational Tuning of GPCR Signaling
Engineering a Model Cell for Rational Tuning of GPCR Signaling
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DOI：
10.1016/j.cell.2019.02.023
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发表时间：
2019-04-18
期刊：
影响因子：
64.5
通讯作者：
Ellis, Tom
中科院分区：
文献类型：
--
作者：
Shaw, William M.;Yamauchi, Hitoshi;Ellis, Tom
G蛋白偶联受体（GPCR）信号转导是真核生物对环境中特定信号做出反应的主要方法。然而，由于天然信号转导结构和表达的多样性，每个GPCR的刺激和反应之间的关系难以预测。利用酵母中的基因组工程，我们构建了一个绝缘的，模块化的GPCR信号转导系统，以研究如何使用合成工具可预测地调节对刺激的反应。我们通过计算和实验重构描绘了一组最小的关键组件的贡献，确定了合理调整剂量反应的简单设计原则。使用五种不同的GPCR，我们展示了这如何使细胞和财团被工程化，以响应与人类健康相关的肽，代谢物和激素的所需浓度。这项工作使细胞传感的合理调整，同时提供了一个框架，以指导在其他系统中基于GPCR的信号重编程。
G protein-coupled receptor (GPCR) signaling is the primary method eukaryotes use to respond to specific cues in their environment. However, the relationship between stimulus and response for each GPCR is difficult to predict due to diversity in natural signal transduction architecture and expression. Using genome engineering in yeast, we constructed an insulated, modular GPCR signs transduction system to study how the response to stimuli can be predictably tuned using synthetic tools. We delineated the contributions of a minimal set of key components via computational and experimental refactoring, identifying simple design principles for rationally tuning the dose response. Using five different GPCRs, we demonstrate how this enables cells and consortia to be engineered to respond to desired concentrations of peptides, metabolites, and hormones relevant to human health. This work enables rational tuning of cell sensing while providing a framework to guide reprogramming of GPCR-based signaling in other systems.