Molecular mechanisms of CBASS phospholipase effector CapV mediated membrane disruption

Jianping Kong, Wanqian Wu, Shiyue Ke, Zihan Zhou, Shenglan Xia, Jianyu Chen, Runyu Zhu, Yijia Hou, Tinashe Makanyire, Xiangru Shan, Zhuyue Zhuo, Keying Li, Hongtao Shen, Pan Yang, Pingping Huang, Jingxian Liu, Jing Li, Xiaolian Sun, Jiajia Dong, Hongbin Sun, Meirong Chen (), Meiling Lu (), Zhaoxing Li () and Yibei Xiao ()
Additional contact information
Jianping Kong: China Pharmaceutical University
Wanqian Wu: China Pharmaceutical University
Shiyue Ke: China Pharmaceutical University
Zihan Zhou: China Pharmaceutical University
Shenglan Xia: China Pharmaceutical University
Jianyu Chen: China Pharmaceutical University
Runyu Zhu: China Pharmaceutical University
Yijia Hou: China Pharmaceutical University
Tinashe Makanyire: China Pharmaceutical University
Xiangru Shan: China Pharmaceutical University
Zhuyue Zhuo: China Pharmaceutical University
Keying Li: China Pharmaceutical University
Hongtao Shen: China Pharmaceutical University
Pan Yang: China Pharmaceutical University
Pingping Huang: China Pharmaceutical University
Jingxian Liu: China Pharmaceutical University
Jing Li: China Pharmaceutical University
Xiaolian Sun: China Pharmaceutical University
Jiajia Dong: Nanjing University Of Chinese Medicine
Hongbin Sun: China Pharmaceutical University
Meirong Chen: China Pharmaceutical University
Meiling Lu: China Pharmaceutical University
Zhaoxing Li: China Pharmaceutical University
Yibei Xiao: China Pharmaceutical University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63658-x

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