高尔基体
信号转导衔接蛋白
刺
干扰素基因刺激剂
细胞生物学
内质网
生物
先天免疫系统
免疫系统
信号转导
免疫学
工程类
航空航天工程
作者
Rutger D. Luteijn,Sypke R. van Terwisga,Jill E. Ver Eecke,Liberty Onia,Shivam A. Zaver,Joshua J. Woodward,Richard Wubbolts,David H. Raulet,Frank J. M. van Kuppeveld
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2024-03-12
卷期号:17 (827)
被引量:1
标识
DOI:10.1126/scisignal.ade3643
摘要
Activation of the endoplasmic reticulum (ER)-resident adaptor protein STING, a component of a cytosolic DNA-sensing pathway, induces the transcription of genes encoding type I interferons (IFNs) and other proinflammatory factors. Because STING is activated at the Golgi apparatus, control of the localization and activation of STING is important in stimulating antiviral and antitumor immune responses. Through a genome-wide CRISPR interference screen, we found that STING activation required the Golgi-resident protein ACBD3, which promotes the generation of phosphatidylinositol 4-phosphate (PI4P) at the trans-Golgi network, as well as other PI4P-associated proteins. Appropriate localization and activation of STING at the Golgi apparatus required ACBD3 and the PI4P-generating kinase PI4KB. In contrast, STING activation was enhanced when the lipid-shuttling protein OSBP, which removes PI4P from the Golgi apparatus, was inhibited by the US Food and Drug Administration-approved antifungal itraconazole. The increase in the abundance of STING-activating phospholipids at the trans-Golgi network resulted in the increased production of IFN-β and other cytokines in THP-1 cells. Furthermore, a mutant STING that could not bind to PI4P failed to traffic from the ER to the Golgi apparatus in response to a STING agonist, whereas forced relocalization of STING to PI4P-enriched areas elicited STING activation in the absence of stimulation with a STING agonist. Thus, PI4P is critical for STING activation, and manipulating PI4P abundance may therapeutically modulate STING-dependent immune responses.
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