A redox switch regulates the assembly and anti-CRISPR activity of AcrIIC1

Yanan Zhao, Jiaojiao Hu, Shan-Shan Yang, Jing Zhong, Jianping Liu, Shuo Wang, Yuzhuo Jiao, Fang Jiang, Ruiyang Zhai, Bingnan Ren, Hua Cong, Yuwei Zhu, Fengtong Han, Jixian Zhang, Yue Xu, Zhiwei Huang, Shengnan Zhang and Fan Yang ()
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Yanan Zhao: Harbin Institute of Technology
Jiaojiao Hu: Chinese Academy of Sciences
Shan-Shan Yang: School of Environment, Harbin Institute of Technology
Jing Zhong: Harbin Institute of Technology
Jianping Liu: Chinese Academy of Sciences
Shuo Wang: Harbin Institute of Technology
Yuzhuo Jiao: Harbin Institute of Technology
Fang Jiang: Harbin Institute of Technology
Ruiyang Zhai: Harbin Institute of Technology
Bingnan Ren: Harbin Institute of Technology
Hua Cong: Harbin Institute of Technology
Yuwei Zhu: Harbin Institute of Technology
Fengtong Han: Harbin Institute of Technology
Jixian Zhang: Harbin Institute of Technology
Yue Xu: Harbin Institute of Technology
Zhiwei Huang: Harbin Institute of Technology
Shengnan Zhang: Chinese Academy of Sciences
Fan Yang: Harbin Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Anti-CRISPRs (Acrs) are natural inhibitors of bacteria’s CRISPR-Cas systems, and have been developed as a safeguard to reduce the off-target effects of CRISPR gene-editing technology. Acrs can directly bind to CRISPR-Cas complexes and inhibit their activities. However, whether this process is under regulation in diverse eukaryotic cellular environments is poorly understood. In this work, we report the discovery of a redox switch for NmeAcrIIC1, which regulates NmeAcrIIC1’s monomer-dimer interconversion and inhibitory activity on Cas9. Further structural studies reveal that a pair of conserved cysteines mediates the formation of inactive NmeAcrIIC1 dimer and directs the redox cycle. The redox switch also applies to the other two AcrIIC1 orthologs. Moreover, by replacing the redox-sensitive cysteines, we generated a robust AcrIIC1 variant that maintains potent inhibitory activity under various redox conditions. Our results reveal a redox-dependent regulation mechanism of Acr, and shed light on the design of superior Acr for CRISPR-Cas systems.

Date: 2022
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DOI: 10.1038/s41467-022-34551-8

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