Zhang Tianyu, Wang Yixuan, Nie Xiaotong, Chen Xiangrong, Jin Yueyi, Sun Lulu, Yang Ruqian, Wang Jie, Xu Wenqing, Song Ting, Xie Wei, Chen Xiangfeng, Li Chaojun, Zhou Jun, Wu Sijin, Li Yan, Li Tianliang
Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, China.
Key Laboratory for Applied Technology of Sophisticated Analytical Instruments, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Science), Jinan, Shandong, China.
Cell Rep. 2025 Mar 25;44(3):115397. doi: 10.1016/j.celrep.2025.115397. Epub 2025 Mar 5.
Inflammation is a crucial element of immune responses, with pivotal roles in host defenses against pathogens. Comprehensive understanding of the molecular mechanisms underlying inflammation is imperative for developing effective strategies to combat infectious diseases. Here, we conducted a screening analysis and identified enkurin domain-containing protein 1 (ENKD1) as a promising regulator of inflammation. We observed that ENKD1 expression was significantly reduced on activation of multiple Toll-like receptor (TLR) molecules. Deletion of ENKD1 resulted in enhanced innate immune system activation and exacerbation of septic inflammation. Mechanistically, ENKD1 interacted with geranylgeranyl diphosphate synthase 1 (GGPS1) and modulated its enzymatic activity, thereby influencing geranylgeranyl diphosphate production. This interaction ultimately led to Ras-related C3 botulinum toxin substrate 1 (RAC1) inactivation and suppression of pro-inflammatory signaling pathways. Our findings establish ENKD1 as a critical regulator of innate immune cell activation, underscoring its significant role in septic inflammation.
炎症是免疫反应的关键要素，在宿主抵御病原体的防御中起关键作用。全面了解炎症背后的分子机制对于制定对抗传染病的有效策略至关重要。在此，我们进行了一项筛选分析，并确定含enkurin结构域蛋白1（ENKD1）是一种有前景的炎症调节因子。我们观察到，在多种Toll样受体（TLR）分子激活时，ENKD1表达显著降低。ENKD1缺失导致先天免疫系统激活增强和脓毒症炎症加剧。从机制上讲，ENKD1与香叶基香叶基二磷酸合酶1（GGPS1）相互作用并调节其酶活性，从而影响香叶基香叶基二磷酸的产生。这种相互作用最终导致Ras相关C3肉毒杆菌毒素底物1（RAC1）失活并抑制促炎信号通路。我们的研究结果确立了ENKD1作为先天免疫细胞激活的关键调节因子，突出了其在脓毒症炎症中的重要作用。
