Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations
Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations
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DOI：
10.1172/jci79100
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发表时间：
2014-12-01
影响因子：
15.9
通讯作者：
Rieux-Laucat, Frederic
中科院分区：
文献类型：
--
作者：
Jeremiah, Nadia;Neven, Benedicte;Rieux-Laucat, Frederic
对病毒感染的天然免疫涉及I型IFN应答的诱导;然而，该途径的功能失调调节导致不适当的炎症。在这里，我们评估了一个非血缘家庭的混合欧洲血统，4名成员受到全身炎症和自身免疫性疾病，包括狼疮，与变量的临床表现。我们在受影响的个体中确定了TMEM 173中的一个生殖系显性功能获得性突变，该突变编码I型IFN基因（STING）的刺激因子。STING是胞质DNA传感途径中的关键信号传导分子，并且STING活化通常需要二聚化，其由响应于胞质DNA的cGAMP合酶产生的2 '3'环GMP-AMP（cGAMP）诱导。结构建模支持基于稳定的二聚化的突变STING蛋白的组成型活化。与模型预测一致，我们发现STING突变体自发地定位于患者成纤维细胞的高尔基体中，并且在体外不存在外源性2 '3'-cGAMP的情况下具有组成型活性。因此，我们观察到升高的血清IFN活性和I型IFN的签名在外周血中受影响的家庭成员。这些发现强调了STING在激活先天性和适应性免疫应答中的关键作用，并暗示了人类狼疮特征中的异常STING激活。
Innate immunity to viral infection involves induction of the type I IFN response; however, dysfunctional regulation of this pathway leads to inappropriate inflammation. Here, we evaluated a nonconsanguineous family of mixed European descent, with 4 members affected by systemic inflammatory and autoimmune conditions, including lupus, with variable clinical expression. We identified a germline dominant gain-of-function mutation in TMEM173, which encodes stimulator of type I IFN gene (STING), in the affected individuals. STING is a key signaling molecule in cytosolic DNA-sensing pathways, and STING activation normally requires dimerization, which is induced by 2'3' cyclic GMP-AMP (cGAMP) produced by the cGAMP synthase in response to cytosolic DNA. Structural modeling supported constitutive activation of the mutant STING protein based on stabilized dimerization. In agreement with the model predictions, we found that the STING mutant spontaneously localizes in the Golgi of patient fibroblasts and is constitutively active in the absence of exogenous 2'3'-cGAMP in vitro. Accordingly, we observed elevated serum IFN activity and a type I IFN signature in peripheral blood from affected family members. These findings highlight the key role of STING in activating both the innate and adaptive immune responses and implicate aberrant STING activation in features of human lupus.