国家纳米科学中心李乐乐团队报道了，串联控制的动态DNA组装实现了cGAS-STING刺激的时间选择性正交调节。相关研究成果于2024年11月11日发表于国际顶尖学术期刊《德国应用化学》。

尽管在生物应用中DNA结构的可控重组方面取得了进展，但缺乏使免疫途径正交调节的策略仍然是一个挑战。

该文中，研究人员首次报道了一种内源性和外源性串联调节的DNA组装策略，该策略能够正交控制环GMP-AMP合酶（cGAS）——干扰素基因刺激因子（STING）途径的刺激。

含有两个回文序列的DNA基序，被改造成一个连接无碱基位点（AP）的阻断序列，以抑制其自组装功能，而无嘌呤/无嘧啶内切酶1（APE1）触发的AP位点的酶切，使DNA基序能够重新配置和自组装成长双链结构，从而实现cGAS催化活性的变构激活，产生2'3'-环GMP AMP用于STING刺激。

重要的是，研究证明APE1调控的DNA组装使细胞选择性激活cGAS-STING信号。此外，通过用可光解基团重新设计DNA基序，酶触发的DNA组装使cGAS–STING刺激起作用（“开启”），而双链DNA的光介导片段能够终止这种刺激（“关闭”），从而实现对免疫调节的正交控制。

该项工作强调了一种内源性和外源性串联调节策略，以正交控制的方式调节cGAS–STING通路。

附：英文原文

Title: Tandem-Controlled Dynamic DNA Assembly Enables Temporally-Selective Orthogonal Regulation of cGAS–STING Stimulation

Author: Xiangfei Li, Fangzhi Yu, Lele Li

Issue&Volume: 2024-11-11

Abstract: Despite advances in the controlled reconfiguration of DNA structures for biological applications, the dearth of strategies that allow for orthogonal regulation of immune pathways remains a challenge. Here, we report for the first time an endogenous and exogenous tandem-regulated DNA assembly strategy that enables orthogonally controlled stimulation of the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway. A DNA motif containing two palindromic sequences is engineered with an abasic site (AP)-connected blocking sequence to inhibit its self-assembly function, while apurinic/apyrimidinic endonuclease 1 (APE1)-triggered enzymatic cleavage of the AP site enables the reconfiguration and self-assembly of DNA motif into long double-stranded structures, thus realizing allosteric activation of the catalytic activity of cGAS to produce 2’3’-cyclic-GMP-AMP for STING stimulation. Importantly, we demonstrate that APE1-regulated DNA assembly allows for cell-selective activation of cGAS–STING signaling. Furthermore, by re-engineering the DNA motif with a photocleavable group, enzyme-triggered DNA assembly allows the cGAS–STING stimulation to operate (switched "ON''), whereas light-mediated fragmentation of the double-stranded DNA enables termination of such stimulation (switched "OFF"), thereby achieving orthogonal control over immune regulation. This work highlights an endogenous and exogenous tandem regulated strategy to modulate the cGAS–STING pathway in an orthogonally controlled manner.

DOI: 10.1002/anie.202417916

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202417916