IMMUNITY
·
2025
·
IF 26.3
Jing Han,Shuhao Zhang,Yanfei Hou,Yi Wang,Zhengyin Zhang,Jiaming Yang,Yifang Xu,Zexu Peng,Hang Yin,Kehong Chen,Xiangyu Liu,Conggang Zhang
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is critical in innate immunity. Recent research has highlighted the importance of phosphatidylinositol 4-phosphate (PI4P) signaling within the Golgi apparatus for STING activation. However, the exact molecular mechanisms by which PI4P regulates STING have remained unclear. Here, we report the activation mechanism of STING triggered by PI4P and a chemical STING agonist, GNE-6468. Utilizing cryoelectron microscopy, we determined that GNE-6468 bound to a distinct pocket within the STING transmembrane (TM) domain, promoting outward movements of the STING TM3 helix without altering the conformation of the ligand-binding domain. Notably, we provided structural insights into STING bound to both PI4P and GNE-6468, and they collectively induced STING oligomerization and STING-mediated immune responses. Functional assays further confirmed that the interactions among STING, PI4P, and GNE-6468 were essential for STING activation. Collectively, these results demonstrate that PI4P and GNE-6468 cooperatively bind STING to activate its signaling, highlighting its therapeutic potential.
研究领域:
免疫学
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结构生物学
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细胞信号传导
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天然免疫
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
ATHEROSCLEROSIS
·
2024
·
IF 4.9
Wang-Xin Liu,Yi-Fan Hu,Guang-Jie Tai,Yan-Ping Li,Jia-Peng Li,Shu Qiu,Rui-Fang Zheng,Xiao-Xue Li,Ming Xu
Background and aims Atherosclerotic cardiovascular disease complicated by diabetes mellitus (DM) is the leading cause of death in diabetic patients, and it is strongly associated with macrophages and inflammasomes. It has been found that activation of NLRP3 inflammasome is closely associated with phosphatidylinositol 4-phosphate (PI4P) on the trans-Golgi. However, how PI4P and NLRP3 regulate macrophage function and its role in diabetic atherosclerotic plaques is unclear. Methods The expression of Pi4p and Nlrp3-inflammasome-related proteins in atherosclerosis in apolipoprotein E-deficient ( Apoe -/- ) and Apoe -/- DM mice were investigated. Then, Pi4p levels were affected by shRNA-Pi4kb or cDNA-Sac1 plasmid to investigate the effects of changes in Pi4p-related metabolic enzymes on macrophage function. Finally, the genetically modified macrophages were injected into diabetic Apoe -/- mice to explore their effects on the pathology of atherosclerosis. Results DM promoted plaque progression in atherosclerotic mice and increased expression of Pi4p and Nlrp3 on plaques. In addition, impaired macrophage function induced by high glucose was reversed by transfected shRNA-Pi4kb or cDNA-Sac1 plasmid. Furthermore, it was demonstrated that decreased levels of Pi4p reduced plaque area in diabetic Apoe -/- mice. Conclusions Taken together, our data suggested that Pi4p/Nlrp3 in macrophages plays an important role in the exacerbation of atherosclerosis in diabetic mice. Pi4p-related metabolizing enzymes (PI4KB and SAC1) may be the potential therapeutic strategy for diabetic atherosclerosis, and macrophage therapy is also a potential treatment.
研究领域:
心血管疾病
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糖尿病
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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2025
·Vol. 11
·期 34
·
IF 12.5
Zhiyi Wang,Jingyi Zhang,Jilei Huang,Gan Sha,Xinyue Song,Xue Cao,Zhenchen Yan,Chuanhe Liu,Siping Chen,Ziying Li,Xiuqin Huang,Qingjun Xie,Xin Yang,Guohui Zhou,Tong Zhang
RNA viruses often remodel host intracellular membranes to establish specialized replication compartments through viral protein–induced phase separation. However, the mechanisms underlying membrane remodeling and the characteristics that render these sites conducive to replication remain poorly understood, particularly in plant negative-strand RNA viruses. Here, we demonstrate that the phosphoprotein (P) of rice stripe mosaic virus (RSMV) forms biomolecular condensates via liquid-liquid phase separation (LLPS) to recruit essential components for viral replication factories (VFs). We identify a direct interaction between RSMV P and adenosine diphosphate (ADP) ribosylation factor 1 (OsARF1C), a crucial regulator of the coatomer protein I (COP I) vesicle transport pathway that is vital for viral replication. This interaction indirectly recruits OsARF1C’s partner, phosphatidylinositol 4-kinase beta (OsPI4KB), which drives localized phosphatidylinositol-4 phosphate (PI4P) synthesis. Concurrently, the P protein modulates its aggregates and LLPS droplets through PI4P, thereby expanding the replication site and enhancing viral replication.
研究领域:
植物病毒学
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分子植物病理学
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病毒复制机制
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细胞生物学
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生物大分子相分离
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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