Antiviral signaling of a type III CRISPR-associated deaminase
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<sub>4</sub> or cA<sub>6</sub>, 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<sub>4</sub> or cA<sub>6</sub> 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.
Authors
- V. Wu (ORCID: https://orcid.org/0000-0002-1257-4154)
- Chunyi Hu (ORCID: https://orcid.org/0000-0003-4509-4840)
- Zhaoxing Li (ORCID: https://orcid.org/0000-0002-6928-9856)
- Meiling Lü (ORCID: https://orcid.org/0000-0001-8738-987X)
- Peng Yang (ORCID: https://orcid.org/0000-0002-2613-941X)
- Shunxiang Li (ORCID: https://orcid.org/0000-0001-9866-6609)
- Yucheng Zhao (ORCID: https://orcid.org/0000-0002-8962-5212)
- Yibei Xiao (ORCID: https://orcid.org/0000-0003-4716-5526)
- Shunli Ji (ORCID: https://orcid.org/0009-0000-5115-0197)
- Jianping Kong (ORCID: https://orcid.org/0000-0001-5091-364X)
- Yijun Chen (ORCID: https://orcid.org/0000-0002-4920-152X)
- Yong Cui (ORCID: https://orcid.org/0000-0002-8613-010X)
- Guanglei Li (ORCID: https://orcid.org/0000-0002-5038-5039)
- Yan Duan
- Meirong Chen (ORCID: https://orcid.org/0000-0003-4315-0204)
- Yutao Li (ORCID: https://orcid.org/0009-0005-6251-815X)
- P. S. Yan (ORCID: https://orcid.org/0009-0000-6008-5278)
- Chenyang Hua
Institutions
- Nanjing University of Finance and Economics (CN)
- Hunan University of Traditional Chinese Medicine (CN)
- China Pharmaceutical University (CN)
- National University of Singapore (SG)
- Chongqing Medical and Pharmaceutical College (CN)
Publication Details
- Journal
- Science
- Published
- 2024-12-12
- DOI
- https://doi.org/10.1126/science.adr0393
- Citations
- 11
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 2.57