Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of intracellular pathogens. However, the role and mechanism of the important lncRNAs in Mycobacterium tuberculosis (M.tb) infection remain largely unexplored. Recently, we found that a secreted M.tb Rv1579c (an early secreted target with a molecular weight of 12 kDa, named EST12) protein activates NLRP3-gasdermin D (GSDMD)-mediated pyroptosis and plays a pivotal role in M.tb-induced immunity. In the present study, M.tb and the EST12 protein negatively regulated the expression of a key lncRNA (named lnc-EST12) in mouse macrophages by activating the JAK2-STAT5a signaling pathway. Lnc-EST12, with a size of 1583 bp, is mainly expressed in immune-related organs (liver, lung and spleen). Lnc-EST12 not only reduces the expression of the proinflammatory cytokines IL-1β, IL-6, and CCL5/8 but also suppresses the NLRP3 inflammasome and GSDMD pyroptosis-IL-1β immune pathway through its interaction with the transcription factor far upstream element-binding protein 3 (FUBP3). The KH3 and KH4 domains of FUBP3 are the critical sites for binding to lnc-EST12. Deficiency of mouse lnc-EST12 or FUBP3 in macrophages increased M.tb clearance and inflammation in mouse macrophages or mice. In conclusion, we report a new immunoregulatory mechanism in which mouse lnc-EST12 negatively regulates anti-M.tb innate immunity through FUBP3.

长非编码 RNA (lncRNA) 与细胞内病原体的发病机制有关。然而，重要的lncRNA在结核分枝杆菌（M.tb ）感染中的作用和机制在很大程度上仍未被探索。最近，我们发现分泌型M.tb Rv1579c（一种分子量为 12 kDa 的早期分泌靶标，命名为 EST12）蛋白可激活 NLRP3-gasdermin D (GSDMD) 介导的细胞焦亡，并在M.tb诱导的细胞焦亡中发挥关键作用免疫。在本研究中，M.tb和EST12蛋白通过激活JAK2-STAT5a信号通路负向调节小鼠巨噬细胞中关键lncRNA（名为lnc-EST12）的表达。Lnc-EST12大小为1583 bp，主要表达于免疫相关器官（肝、肺、脾）。Lnc-EST12不仅降低促炎细胞因子IL-1β、IL-6和CCL5/8的表达，而且通过与转录因子远上游元件的相互作用抑制NLRP3炎性体和GSDMD焦亡-IL-1β免疫通路。结合蛋白 3 (FUBP3)。FUBP3 的 KH3 和 KH4 结构域是与 lnc-EST12 结合的关键位点。巨噬细胞中小鼠 lnc-EST12 或 FUBP3 的缺乏会增加小鼠巨噬细胞或小鼠中M.tb 的清除和炎症。总之，我们报告了一种新的免疫调节机制，其中小鼠lnc-EST12通过FUBP3负调节抗结核分枝杆菌先天免疫。