2. Academic Validation
  3. ENKD1 modulates innate immune responses through enhanced geranylgeranyl pyrophosphate synthase activity

ENKD1 modulates innate immune responses through enhanced geranylgeranyl pyrophosphate synthase activity

  • Cell Rep. 2025 Mar 25;44(3):115397. doi: 10.1016/j.celrep.2025.115397.
Tianyu Zhang 1,  Yixuan Wang 1,  Xiaotong Nie 1,  Xiangrong Chen 2,  Yueyi Jin 3,  Lulu Sun 1,  Ruqian Yang 1,  Jie Wang 1,  Wenqing Xu 1,  Ting Song 1,  Wei Xie 4,  Xiangfeng Chen 2,  Chaojun Li 5,  Jun Zhou 6,  Sijin Wu 7,  Yan Li 8,  Tianliang Li 9
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou 215123, China.
  • 4 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine and School of Medicine, Nanjing University, Nanjing, Jiangsu 210093, China.
  • 6 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; State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 7 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou 215123, China. Electronic address: sijin.wu@xjtlu.edu.cn.
  • 8 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. Electronic address: yanli@sdnu.edu.cn.
  • 9 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. Electronic address: li.tianliang@outlook.com.
PMID: 40048432 DOI: 10.1016/j.celrep.2025.115397
Abstract

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.

Keywords

CP: Immunology; ENKD1; GGPS1; RAC1; Toll-like receptor; inflammation; sepsis.

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