2026年9月5日，美国斯坦福大学Steven M. Banik等科学家在《细胞》发表研究，开发了一种将蛋白质降解转化为转录输出的合成电路，实现比例转录激活并应用于药物发现。

细胞可以通过转录输出来响应特定蛋白质丰度的变化。受天然转录后电路启发的合成方法，能够将蛋白质丰度变化转化为可编程基因表达，这将具有变革性意义。在此，研究人员发现并描述了将活细胞中蛋白质降解有效转化为转录输出的设计原理。他们定义了比例转录激活，即通过对转录因子与其抑制剂融合的靶蛋白之间比率的控制，能够以高灵敏度大规模检测丰度变化。研究表明，比例转录激活可以在单细胞中使用三重正交电路或在多细胞池中实现，其运作独立于蛋白质下调机制，并能通过细胞存活、荧光蛋白表达或条形码测序等输出方式同时检测多个蛋白质下调事件。这些电路可应用于致癌靶点，并能助力发现新的分子胶降解剂。

附：英文原文

Title: Ratiometric transcriptional activation by protein degradation

Author: Melissa A. Gray, Katelyn L. Randal, Jennifer A. Co, Michelle T. Tang, Athena Z. Xue, Sophia W. Chen, Hlib Razumkov, Qusay Q. Omran, David E. Solow-Cordero, Jeonghye Yu, Stephanie A. Robinson, Cara A. Starnbach, Nathanael S. Gray, Steven M. Corsello, Steven M. Banik

Issue&Volume:

Abstract: Cells can respond to alterations in the abundances of specific proteins through transcriptional outputs. Synthetic approaches inspired by native post-transcriptional circuits that convert protein abundance changes into programmable gene expression would be transformative. Here, we discover and describe design principles that effectively convert protein degradation into transcriptional outputs in live cells. We define ratiometric transcriptional activation, where control over the ratio between a transcription factor and a protein of interest fused to its inhibitor enables detection of abundance changes with high sensitivity at scale. We show that ratiometric transcriptional activation can be implemented in single cells using triply orthogonal circuits or in multicellular pools, operating independently of the mechanism of protein downregulation and enabling simultaneous detection of multiple protein downregulation events through outputs such as cell survival, fluorescent protein expression, or barcode sequencing. These circuits can be applied to oncogenic targets and enable discovery of new molecular glue degraders.

DOI: 10.1016/j.cell.2026.08.009

Source: https://www.cell.com/cell/abstract/S0092-8674(26)00936-0