Antiviral signaling of a type III CRISPR-associated deaminase

• 成果类型: Article
• 署名作者: Li, Yutao; Li, Zhaoxing; Yan, Purui; Hua, Chenyang; Kong, Jianping; Wu, Wanqian; Cui, Yurong; Duan, Yan; Li, Shunxiang; Li, Guanglei; Ji, Shunli; Chen, Yijun; Zhao, Yucheng; Yang, Peng; Hu, Chunyi; Lu, Meiling; Chen, Meirong; Xiao, Yibei
• 署名单位: China Pharmaceutical University; China Pharmaceutical University; China Pharmaceutical University; China Pharmaceutical University; Hunan University of Chinese Medicine; Nanjing University of Finance & Economics; China Pharmaceutical University; National University of Singapore; National University of Singapore
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11967
• DOI: 10.1126/science.adr0393
• 发表日期: 2025-02-21
• 页码: 841-+
• 关键词: adenosine-deaminase; dna cleavage; protein; degradation; STABILITY; immunity

摘要

Prokaryotes have evolved diverse defense strategies against viral infection, including foreign nucleic acid degradation by CRISPR-Cas systems and DNA and RNA synthesis inhibition through nucleotide pool depletion. Here, we report an antiviral mechanism of type III CRISPR-Cas-regulated adenosine triphosphate (ATP) depletion in which ATP is converted into inosine triphosphate (ITP) by CRISPR-Cas-associated adenosine deaminase (CAAD) upon activation by either cA(4) or cA(6), followed by hydrolysis into inosine monophosphate (IMP) by Nudix hydrolase, ultimately resulting in cell growth arrest. The cryo-electron microscopy structures of CAAD in its apo and activated forms, together with biochemical evidence, revealed how cA(4) or cA(6) binds to the CRISPR-associated Rossmann fold (CARF) domain and abrogates CAAD autoinhibition, inducing substantial conformational changes that reshape the structure of CAAD and induce its deaminase activity. Our results reveal the mechanism of a CRISPR-Cas-regulated ATP depletion antiviral strategy.