Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING
Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING
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DOI：
10.1096/fj.201601093r
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发表时间：
2017-07-01
期刊：
影响因子：
4.8
通讯作者：
Guzman, Carlos A.
中科院分区：
文献类型：
--
作者：
Rueckert, Christine;Rand, Ulfert;Guzman, Carlos A.
环二核苷酸GMP AMP （cGAMP）和c-二-AMP[双-(3',5')-环二聚体AMP]是通过STING-TBK1-IRF3级联有效的I型IFN诱导剂。在不同的临床前模型中，它们是促进抗原特异性体液和细胞免疫反应的有希望的佐剂；然而，疫苗接种的最佳结果取决于平衡的免疫激活。在此，我们以小鼠原代树突状细胞为基础，在体外模型中表征了c-di-AMP和cGAMP诱导ifn - β的过程。结果显示，延长细胞刺激后，ifn - β的产生减少。我们证明这种作用依赖于c-di-AMP/ cgamp介导的IFN刺激因子（STING）蛋白水平的下调。这些结果被人外周血单个核细胞衍生的树突状细胞证实。为探索STING调节的潜在机制所进行的研究表明，蛋白质水解降解是观察到的细胞STING水平下降的一个因素。Rueckert， C, Rand， U, Roy， U, Kasmapour， B., Strowig， T., Guzman， C. a .我们的工作有助于阐明疫苗成分的分子作用模式，这反过来又是合理设计具有可预测功效和安全性的疫苗的先决条件。
The cyclic dinucleotides, GMP AMP (cGAMP) and c-di-AMP [bis-(3',5')-cyclic dimeric AMP], are potent type I IFN inducers via STING-TBK1-IRF3 cascade. They are promising adjuvants that promote antigen-specific humoral and cellular immune responses in different preclinical models; however, an optimal outcome of vaccination depends on a balanced immune activation. Here, we characterize the process of IFN-beta induction by c-di-AMP and cGAMP in an in vitro model on the basis of primary mouse dendritic cells. Results obtained show decreased IFN-beta production upon prolonged cell stimulation. We demonstrate that this effect depends on c-di-AMP/cGAMP-mediated down-regulation of stimulator of IFN gene (STING) protein levels. These results were confirmed by using human peripheral blood mononuclear cell derived dendritic cells. Studies performed to explore the potential mechanism of STING modulation suggested proteolytic degradation to be a contributing factor to the observed decrease in cellular STING levels. Our work contributes to the elucidation of the molecular mode of action of vaccine constituents, which, in turn, is a prerequisite for the rational design of vaccines with predictable efficacy and safety profiles Rueckert, C., Rand, U., Roy, U., Kasmapour, B., Strowig, T., Guzman, C. A. Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING.