Engineering synthetic phosphorylation signaling networks in human cells.
Engineering synthetic phosphorylation signaling networks in human cells.
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在人体细胞中工程合成磷酸化信号网络。
DOI：
10.1101/2023.09.11.557100
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Bashor,CalebJ
中科院分区：
文献类型：
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作者：
Yang,Xiaoyu;Rocks,JasonW;Jiang,Kaiyi;Walters,AndrewJ;Rai,Kshitij;Liu,Jing;Nguyen,Jason;Olson,ScottD;Mehta,Pankaj;Collins,JamesJ;Daringer,NicholeM;Bashor,CalebJ
蛋白质磷酸化信号网络在细胞如何感知和响应环境中起着核心作用。我们设计了人工磷酸化网络，其中可逆的酶促磷酸化循环由模块化蛋白质结构域部分组装而成，并连接在一起以在人类细胞中创建合成磷酸化回路。我们的设计方案实现了电路功能的模型指导调谐和进行不同网络连接的能力;合成磷酸化电路可以耦合到上游细胞表面受体，以实现细胞外配体的快速时间尺度传感，下游连接可以调节基因表达。我们设计了基于细胞的细胞因子控制器，可以动态感知和抑制活化的T细胞。我们的工作介绍了一种可推广的方法，允许设计的信号电路，使用户定义的传感和响应功能的各种生物传感和治疗应用。
Protein phosphorylation signaling networks have a central role in how cells sense and respond to their environment. We engineered artificial phosphorylation networks in which reversible enzymatic phosphorylation cycles were assembled from modular protein domain parts and wired together to create synthetic phosphorylation circuits in human cells. Our design scheme enabled model-guided tuning of circuit function and the ability to make diverse network connections; synthetic phosphorylation circuits can be coupled to upstream cell surface receptors to enable fast-timescale sensing of extracellular ligands, and downstream connections can regulate gene expression. We engineered cell-based cytokine controllers that dynamically sense and suppress activated T cells. Our work introduces a generalizable approach that allows the design of signaling circuits that enable user-defined sense-and-respond function for diverse biosensing and therapeutic applications.