Molecular mechanisms of CBASS phospholipase effector CapV mediated membrane disruption
Cyclic oligonucleotide-based antiphage signaling systems (CBASS) are widespread bacterial immune systems that trigger host suicide via cyclic nucleotide-activated effectors. The predominant strategy to induce cell death in CBASS is membrane disruption. Here, we demonstrate that patatin-like phospholipase CapV, the most abundant CBASS effector, relocates and cleaves membrane phospholipids at the cell pole upon 3'3'-cGAMP binding, inducing polarized membrane disruption and cell death. Using cryo-EM, we reveal that apo-CapV adopts both dimeric and tetrameric states, with its phospholipid-binding pocket occluded and locked in an inactive conformation. Binding to 3'3'-cGAMP induces filamentation and substantial conformational change of CapV, enhancing membrane binding via electrostatic interactions between its interspaced basic surfaces and the negatively charged phosphate moieties of phospholipids. Simultaneously, the rearrangement opens the phospholipid-binding pocket, enabling the accommodation of two fatty acid chains of phospholipid within distinct hydrophobic pockets. Our findings reveal a filament-dependent activation mechanism for phospholipase-mediated membrane disruption during antiviral response.
Authors
- V. Wu (ORCID: https://orcid.org/0000-0002-1257-4154)
- Zihan Zhou (ORCID: https://orcid.org/0000-0002-1697-2168)
- Zhaoxing Li (ORCID: https://orcid.org/0000-0002-6928-9856)
- Yijia Hou
- Keying Li
- Meiling Lü (ORCID: https://orcid.org/0000-0001-8738-987X)
- Ruiyan Zhu (ORCID: https://orcid.org/0000-0002-0787-7337)
- Jianyu Chen (ORCID: https://orcid.org/0000-0003-2578-6524)
- Zong-Yan Zhuo
- Xiaolian Sun (ORCID: https://orcid.org/0000-0001-9549-4741)
- Yibei Xiao (ORCID: https://orcid.org/0000-0003-4716-5526)
- Jianping Kong (ORCID: https://orcid.org/0000-0001-5091-364X)
- Jingxian Liu (ORCID: https://orcid.org/0000-0003-4194-5273)
- Jing Li (ORCID: https://orcid.org/0000-0001-9972-0160)
- Hongbin Sun (ORCID: https://orcid.org/0000-0002-7712-0655)
- Pingping Huang (ORCID: https://orcid.org/0000-0003-0191-2610)
- Yang Pan (ORCID: https://orcid.org/0009-0001-4594-3948)
- Hongtao Shen (ORCID: https://orcid.org/0000-0003-1014-2830)
- Jiajia Dong (ORCID: https://orcid.org/0000-0002-2233-754X)
- Meirong Chen (ORCID: https://orcid.org/0000-0003-4315-0204)
- Ke Shi (ORCID: https://orcid.org/0000-0002-8213-3469)
- S. Xia
- Xinyang Shan
- Tinashe Makanyire
Institutions
- Nanjing University of Chinese Medicine (CN)
- Chongqing University (CN)
- China Pharmaceutical University (CN)
- Chongqing Medical and Pharmaceutical College (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1038/s41467-025-63658-x
- Citations
- 3
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 3.45
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Government of Jiangsu Province
- Shanghai Jiao Tong University
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities