2. Academic Validation
  3. ERAdP facilitates biogenesis of dense core vesicles in Paneth cells to enhance intestinal defense

ERAdP facilitates biogenesis of dense core vesicles in Paneth cells to enhance intestinal defense

  • J Exp Med. 2026 Feb 2;223(2):e20251051. doi: 10.1084/jem.20251051.
Cunzhen Li # 1 2,  Zhen Xiong # 1,  Deyuan Kong # 3 4,  Yuwei Xu 1,  Runyuan Wu 1 2,  Peikang Zhang 1 2,  Ziqi Xiao 1 2,  Hui Guo 1,  Ying Du 1,  JinSong Li 5,  Yun Chen 3 4,  Qiang Zhan 6 7,  Zusen Fan 1 6 8 2
Affiliations

Affiliations

  • 1 State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences , Beijing, China.
  • 2 University of Chinese Academy of Sciences , Beijing, China.
  • 3 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center , Wuxi, China.
  • 4 Department of Immunology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
  • 5 Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences , Shanghai, China.
  • 6 Departments of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
  • 7 Jiangsu Branch of the National Clinical Research Center for Digestive Diseases , Wuxi, China.
  • 8 Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology , Shenzhen, China.
  • # Contributed equally.
PMID: 41474967 DOI: 10.1084/jem.20251051
Abstract

Paneth cells secrete antimicrobial peptides (AMPs) to modulate composition of gut microbiota and host defense. AMPs are typically packaged into dense core vesicles (DCVs) and secreted into the intestinal lumen. However, the mechanisms underlying DCV biogenesis and secretion are still elusive. Here we identified that ERAdP was highly expressed in Paneth cells that acted as a sensor for a Bacterial second messenger c-di-AMP. ERAdP deficiency caused impaired DCV biogenesis and dysfunction of Paneth cells. Mechanistically, by sensing c-di-AMP, ERAdP interacted with NLRP6 and further recruited AnxA2 onto the DCV membrane in Paneth cells. The ERAdP-NLRP6-ANXA2 complex facilitated DCV biogenesis, which enhanced Antibacterial ability of intestines. Disruption of ERAdP-NLRP6-ANXA2 axis led to loss of DCVs in Paneth cells and increased susceptibility to Bacterial infection. Of note, ERAdP-NLRP6-ANXA2 proteins were lowly expressed in IBD patients, and c-di-AMP treatment enhanced Antibacterial capacity in antibiotic-treated mice. Our findings reveal that c-di-AMP stimulation might provide a potential therapeutic strategy for infectious disease and gut inflammation.

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