近日，中国药科大学
研究人员表示，原核生物已经进化出多种防御病毒感染的策略，例如通过CRISPR-Cas系统降解外源核酸，和通过核苷酸池耗尽抑制DNA/RNA合成。
课题组人员报道了III型CRISPR-Cas调控的ATP耗竭的抗病毒机制，其中ATP在被cA4或cA6激活后被CRISPR-Cas相关的腺苷脱氨酶（CAAD）转化为ITP，随后被Nudix水解酶水解为IMP，最终导致细胞生长停滞。
载脂蛋白CAAD和活化CAAD的低温电镜结构，以及生化证据，揭示了cA4/cA6如何结合到CARF结构域并消除CAAD的自抑制作用，诱导大量构象变化，重塑CAAD的结构并诱导其脱氨酶活性。他们的研究结果揭示了CRISPR-Cas调控的ATP耗尽抗病毒策略的机制。
附：英文原文
Title: Antiviral signaling of a type III CRISPR-associated deaminase
Author: Yutao Li, Zhaoxing Li, Purui Yan, Chenyang Hua, Jianping Kong, Wanqian Wu, Yurong Cui, Yan Duan, Shunxiang Li, Guanglei Li, Shunli Ji, Yijun Chen, Yucheng Zhao, Peng Yang, Chunyi Hu, Meiling Lu, Meirong Chen, Yibei Xiao
Issue&Volume: 2024-12-12
Abstract: Prokaryotes have evolved diverse defense strategies against viral infection, such as foreign nucleic acid degradation by CRISPR-Cas systems and DNA/RNA synthesis inhibition via nucleotide pool depletion. Here, we report an antiviral mechanism of type III CRISPR-Cas-regulated ATP depletion, where ATP is converted into ITP by CRISPR-Cas-associated adenosine deaminase (CAAD) upon activation by either cA4 or cA6, followed by hydrolysis into 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 cA4/cA6 binds to the 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.
DOI: adr0393
Source: https://www.science.org/doi/10.1126/science.adr0393