浙江大学曹雪涛等研究人员合作发现，核腺苷激活hnRNPA2B1来增强抗菌性固有免疫。相关论文于2025年1月14日在线发表在《细胞—代谢》杂志上。

研究人员报告了异质核核糖核蛋白A2B1（hnRNPA2B1）是腺苷代谢物的传感器，通过增加Il1b转录来启动抗菌固有免疫反应。髓系细胞特异性Hnrnpa2b1-cKO小鼠对细菌感染更易感，而补充白介素1β（IL-1β）可以挽救这一表型。通过大规模代谢物- hnRNPA2B1相互作用筛选，研究人员发现腺苷直接结合并激活hnRNPA2B1，以介导固有的抗菌反应。

在机制上，腺苷直接招募hnRNPA2B1到Il1b增强子，hnRNPA2B1通过结合和招募核仁蛋白和脂肪质量及肥胖相关蛋白（FTO）来增加Il1b增强子染色质的可及性，从而介导Il1b增强子DNA的N⁶-甲基腺苷（6mA）去甲基化。

此外，细菌感染在感染早期提高了核腺苷的水平，体内腺苷给药通过hnRNPA2B1-IL-1β回路保护小鼠免受细菌感染的死亡。该研究为代谢-表观遗传相互作用提供了新的见解，并揭示了与抗菌固有免疫相关的潜在治疗细菌感染的方法。

据悉，细菌感染会重编程细胞代谢和表观遗传状态，但代谢-表观遗传的相互作用如何增强宿主的抗菌免疫反应仍不明确。

附：英文原文

Title: Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity

Author: Shihao Zhang, Zenghui Cui, Danni Zhang, Deyu Zhang, Ke Jin, Zemeng Li, Bo Li, Boyi Cong, Juan Liu, Lei Wang, Mingyue Wen, Xuetao Cao

Issue&Volume: 2025-01-14

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.

DOI: 10.1016/j.cmet.2024.11.014

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00482-0