2. Academic Validation
  3. Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity

Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity

  • Cell Metab. 2025 Feb 4;37(2):413-428.e7. doi: 10.1016/j.cmet.2024.11.014.
Shihao Zhang 1,  Zenghui Cui 2,  Danni Zhang 3,  Deyu Zhang 2,  Ke Jin 3,  Zemeng Li 4,  Bo Li 2,  Boyi Cong 2,  Juan Liu 4,  Lei Wang 5,  Mingyue Wen 6,  Xuetao Cao 7
Affiliations

Affiliations

  • 1 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China.
  • 2 Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 3 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 4 National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China.
  • 5 Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
  • 6 National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China; Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China; Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou 215123, China. Electronic address: wenmy@immunol.org.
  • 7 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China; Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China; Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China. Electronic address: caoxt@immunol.org.
PMID: 39814017 DOI: 10.1016/j.cmet.2024.11.014
Abstract

Bacterial infection reprograms cellular metabolism and epigenetic status, but how the metabolic-epigenetic crosstalk empowers host Antibacterial defense remains unclear. Here, we report that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is a sensor for metabolite adenine to launch an antimicrobial innate response through increasing Il1b transcription. Myeloid cell-specific Hnrnpa2b1-cKO mice are more susceptible to Bacterial infection, while interleukin 1 beta (IL-1β) supplementation rescues the phenotype. Through a large-scale metabolites-hnRNPA2B1 interaction screen, we reveal that adenine directly binds and activates hnRNPA2B1 to mediate innate Antibacterial response. Mechanistically, adenine directly recruits hnRNPA2B1 to Il1b enhancers, and hnRNPA2B1 increases Il1b enhancer chromatin accessibility through binding and recruiting nucleolin and fat mass and obesity-associated protein (FTO) to mediate Il1b enhancer DNA N6-methyladenosine (6mA) demethylation. Furthermore, Bacterial infection elevates nuclear adenine at the early stage of Infection, and in vivo adenine administration protects mice from death upon Bacterial infection through the hnRNPA2B1-IL-1β circuit. Our findings offer new insights into metabolic-epigenetic crosstalk relevant to Antibacterial innate immunity and indicate potential approaches for treating Bacterial infections.

Keywords

DNA N(6)-methyladenosine; adenine; antibacterial immunity; hnRNPA2B1; interleukin 1; nucleolin.

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