2. Academic Validation
  3. Eukaryotic ADCY7 catalyzes the production of c-di-AMP to activate the NLRP3 inflammasome

Eukaryotic ADCY7 catalyzes the production of c-di-AMP to activate the NLRP3 inflammasome

  • Nat Chem Biol. 2025 May 26. doi: 10.1038/s41589-025-01919-y.
Qiannv Liu # 1 2 3,  Zhiheng Tang # 2 4,  Yan Qian 1 2 3,  Chunlei Wang 1 2 3,  Chun Kong 1 2 3,  Mengqian Li 1 2 3,  Xiangyang Geng 1 2 3,  Yan Zhang 1 2 3,  Xiangyun Cheng 5 6,  Chao Ren 7,  Kai Wang 1 2 3,  Lin Bai 8,  Lin Wang 4,  Dong Jiang 5 6,  Shuo Wang 9,  Xiaoyun Liu 10 11 12,  Pengyan Xia 13 14 15 16
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 2 NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
  • 3 Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, Peking University, Beijing, China.
  • 4 Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 5 Department of Sports Medicine, Peking University Third Hospital, Beijing, China.
  • 6 Beijing Key Laboratory of Sports Injuries, Institute of Sports Medicine of Peking University, Beijing, China.
  • 7 Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
  • 8 Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 9 CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. wangshuo@im.ac.cn.
  • 10 NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China. xiaoyun.liu@bjmu.edu.cn.
  • 11 Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China. xiaoyun.liu@bjmu.edu.cn.
  • 12 Department of Infectious Diseases, Peking University Third Hospital, Beijing, China. xiaoyun.liu@bjmu.edu.cn.
  • 13 Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China. xiap@pku.edu.cn.
  • 14 NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China. xiap@pku.edu.cn.
  • 15 Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, Peking University, Beijing, China. xiap@pku.edu.cn.
  • 16 PUHSC Primary Immunodeficiency Research Center, Peking University, Beijing, China. xiap@pku.edu.cn.
  • # Contributed equally.
PMID: 40419769 DOI: 10.1038/s41589-025-01919-y
Abstract

Toll-like Receptor 9 (TLR9) agonists cause activation of nucleotide-binding domain, leucine-rich repeat protein 3 (NLRP3) inflammasomes but the mechanism is not clear. We found that there is a second signal downstream of TLR9 that induces NLRP3 inflammasome activation. Through screening, Adenylate Cyclase 7 (ADCY7) was found to be an essential regulator of this process. In cells with Adcy7 deficiency, TLR9 agonists were no longer able to activate the NLRP3 inflammasome. ADCY7 not only catalyzes the generation of cyclic adenosine monophosphate (cAMP) but also catalyzes the synthesis of its dimeric form (c-di-AMP). Moreover, c-di-AMP promotes assembly and maturation of the inflammasome by directly binding to NLRP3. Cells with Adcy7 deletion or mutations impacting enzymatic activity cannot produce c-di-AMP. The survival of Adcy7-deficient mice in acute liver injury was also improved. In summary, we found that ADCY7 is required for NLRP3 inflammasome activation downstream of TLR9 by catalyzing the generation of c-di-AMP, which may serve as a target for controlling inflammatory responses in sterile infections.

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