2. Academic Validation
  3. Cyclic-dinucleotide-induced filamentous assembly of phospholipases governs broad CBASS immunity

Cyclic-dinucleotide-induced filamentous assembly of phospholipases governs broad CBASS immunity

  • Cell. 2025 Jul 10;188(14):3744-3756.e16. doi: 10.1016/j.cell.2025.04.022.
Jingge Wang 1,  Zhao Li 1,  Hao Lang 2,  Wenfeng Fu 2,  Yina Gao 3,  Sen Yin 1,  Panpan Sun 2,  Zhaolong Li 2,  Jiafeng Huang 3,  Songqing Liu 3,  Yun Zhu 3,  Fei Sun 4,  Dong Li 2,  Pu Gao 5,  Ang Gao 6
Affiliations

Affiliations

  • 1 Department of Radiology, Zhuhai People's Hospital, The Affiliated Hospital of Beijing Institute of Technology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
  • 2 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 4 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China.
  • 5 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: gaopu@ibp.ac.cn.
  • 6 Department of Radiology, Zhuhai People's Hospital, The Affiliated Hospital of Beijing Institute of Technology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China; Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250118, China; Center for Cell and Gene Therapy, The First Hospital of China Medical University, Shenyang 110001, China. Electronic address: ang.gao@bit.edu.cn.
PMID: 40345202 DOI: 10.1016/j.cell.2025.04.022
Abstract

Cyclic-oligonucleotide-based antiphage signaling systems (CBASS), a widespread antiviral Bacterial immune system homologous to the mammalian cGAS-STING pathway, synthesizes cyclic nucleotide signals and triggers effector proteins to induce cell death and prevent viral propagation. Among various CBASS effectors, Phospholipase effectors are the first to be discovered and are one of the most widespread families that sense cyclic dinucleotides to degrade cell membrane Phospholipids. Here, we report that CBASS phospholipases assemble from a dimeric inactive state into active higher-order filamentous oligomers upon sensing cyclic dinucleotides. Using a combined approach of cryo-electron microscopy and X-ray crystallography, we have determined the structures of CBASS Phospholipase in the inactive dimeric state, the cyclic-dinucleotide-bound active higher-order state, and the substrate-analog-bound catalytic mimicry state, thereby visualizing the complete conformational reorganization process. Complemented by functional assays of intermolecular binding, Phospholipase enzymatic activity, in vitro membrane disruption, and in vivo antiphage efficiency, our work elucidates the mechanisms of assembly and activation of CBASS phospholipases.

Keywords

CBASS; CapE; CapV; antiphage defense system; cGAS; cell death; cyclic dinucleotide; filament; phospholipase.

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