Tang Eric D, Wang Cun-Yu
Laboratory of Molecular Signaling, Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, CA, United States of America.
PLoS One. 2015 Mar 19;10(3):e0120090. doi: 10.1371/journal.pone.0120090. eCollection 2015.
The production of cytokines by the immune system in response to cytosolic DNA plays an important role in host defense, autoimmune disease, and cancer immunogenicity. Recently a cytosolic DNA signaling pathway that is dependent on the endoplasmic reticulum adaptor and cyclic dinucleotide sensor protein STING has been identified. Association of cytosolic DNA with cyclic-GMP-AMP synthase (cGAS) activates its enzymatic activity to synthesize the cyclic dinucleotide second messenger cGAMP from GTP and ATP. Direct detection of cGAMP by STING triggers the activation of IRF3 and NF-kB, and the production of type I interferons and proinflammatory cytokines. The mechanism of how STING is able to mediate downstream signaling remains incompletely understood although it has been shown that dimerization is a prerequisite. Here, we identify a single amino acid change in STING that confers constitutive active signaling. This mutation appears to both enhance ability of STING to both dimerize and associate with its downstream target TBK1.
免疫系统针对胞质DNA产生细胞因子，这在宿主防御、自身免疫性疾病和癌症免疫原性方面发挥着重要作用。最近，一种依赖内质网衔接蛋白和环二核苷酸传感器蛋白STING的胞质DNA信号通路已被确定。胞质DNA与环磷酸鸟苷-腺苷合成酶（cGAS）结合，激活其酶活性，从鸟苷三磷酸（GTP）和三磷酸腺苷（ATP）合成环二核苷酸第二信使cGAMP。STING直接检测cGAMP会触发干扰素调节因子3（IRF3）和核因子κB（NF-κB）的激活，以及I型干扰素和促炎细胞因子的产生。尽管已经表明二聚化是一个先决条件，但STING如何介导下游信号传导的机制仍未完全了解。在这里，我们在STING中鉴定出一个导致组成型活性信号传导的单氨基酸变化。该突变似乎既增强了STING二聚化的能力，又增强了其与下游靶点TANK结合激酶1（TBK1）结合的能力。
