Wen Xuehuan, Bai Songjie, Xiong Guirun, Xiu Huiqing, Li Jiahui, Yang Jie, Yu Qing, Li Bingyu, Hu Ruomeng, Cao Lanxin, Cai Zhijian, Zhang Shufang, Zhang Gensheng
Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Oncology, The Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
J Biol Chem. 2025 Jan;301(1):108085. doi: 10.1016/j.jbc.2024.108085. Epub 2024 Dec 13.
UBE2M, an essential neddylation E2 enzyme, has been implicated in the pathogenesis of various diseases, including cancers, viral infections, and obesity. However, whether UBE2M is involved in the pathogenesis of bacterial sepsis remains unclear. In an Escherichia coli (E. coli)-induced sepsis mouse model, increased UBE2M expression in macrophages in liver and lung tissues postinfection was observed. To further clarify the role of UBE2M in macrophages, mice with macrophage-specific deletion of UBE2M (LysmUbe2m) were constructed. Compared with control mice, these mice presented decreased levels of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α; reduced sepsis-induced organ injury; and improved survival. Notably, macrophage-specific deletion of UBE2M did not impair E. coli clearance. In vitro experiments also revealed that UBE2M-deficient macrophages produced fewer proinflammatory cytokines after E. coli infection without hindering E. coli clearance. RNA-sequencing analysis revealed that UBE2M deletion in macrophages after lipopolysaccharide stimulation notably suppressed transcriptional activation within the JAK-STAT and Toll-like receptor signaling pathways, which was further confirmed by gene set enrichment analysis. Additionally, Western blotting results confirmed that UBE2M deletion inhibited the activation of the NF-κB, ERK, and JAK-STAT signaling pathways. In conclusion, our findings indicate that specific deletion of UBE2M in macrophages protects against E. coli-induced sepsis by downregulating the excessive inflammatory response, potentially providing a novel strategy against sepsis by targeting UBE2M.
UBE2M是一种必需的泛素化E2酶，已被证明与包括癌症、病毒感染和肥胖症在内的多种疾病的发病机制有关。然而，UBE2M是否参与细菌性败血症的发病机制仍不清楚。在大肠杆菌诱导的败血症小鼠模型中，观察到感染后肝脏和肺组织中巨噬细胞的UBE2M表达增加。为了进一步阐明UBE2M在巨噬细胞中的作用，构建了巨噬细胞特异性缺失UBE2M的小鼠（LysmUbe2m）。与对照小鼠相比，这些小鼠促炎细胞因子如IL-1β、IL-6和TNF-α的水平降低；败血症诱导的器官损伤减轻；存活率提高。值得注意的是，巨噬细胞特异性缺失UBE2M并不损害大肠杆菌的清除。体外实验还表明，UBE2M缺陷型巨噬细胞在大肠杆菌感染后产生的促炎细胞因子较少，且不影响大肠杆菌的清除。RNA测序分析显示，脂多糖刺激后巨噬细胞中UBE2M的缺失显著抑制了JAK-STAT和Toll样受体信号通路内的转录激活，基因集富集分析进一步证实了这一点。此外，蛋白质印迹结果证实，UBE2M的缺失抑制了NF-κB、ERK和JAK-STAT信号通路的激活。总之，我们的研究结果表明，巨噬细胞中UBE2M的特异性缺失通过下调过度的炎症反应来预防大肠杆菌诱导的败血症，这可能为通过靶向UBE2M治疗败血症提供一种新策略。
