Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling.
Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling.
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DOI：
10.1084/jem.20200600
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发表时间：
2020-11-02
期刊：
影响因子：
--
通讯作者：
Frémond ML
中科院分区：
文献类型：
--
作者：
Lepelley A;Martin-Niclós MJ;Le Bihan M;Marsh JA;Uggenti C;Rice GI;Bondet V;Duffy D;Hertzog J;Rehwinkel J;Amselem S;Boulisfane-El Khalifi S;Brennan M;Carter E;Chatenoud L;Chhun S;Coulomb l'Hermine A;Depp M;Legendre M;Mackenzie KJ;Marey J;McDougall C;McKenzie KJ;Molina TJ;Neven B;Seabra L;Thumerelle C;Wislez M;Nathan N;Manel N;Crow YJ;Frémond ML
COPA中的杂合错义突变是通过STING的组成性干扰素信号传导的基础，从而定义了一种新的I型干扰素病，并强调了ER-高尔基体轴在干扰素稳态中的重要性。基于这些结果，三名患者接受了干扰素信号传导（JAK1）抑制剂治疗。由于STING（IFN信号传导的关键衔接子）的功能获得性，外被蛋白α亚基（COPA）中的杂合错义突变导致临床上与I型IFN介导的疾病重叠的综合征。最近，在COPA综合征中描述了IFN刺激基因（ISG）水平的增加。然而，COPA突变和IFN信号之间的联系是未知的。我们观察到有症状的COPA患者血液中ISGs和IFN-α水平升高。在体外，突变COPA的过表达和沉默COPA诱导STING依赖性IFN信号转导。我们检测到COPA和STING之间的相互作用，突变COPA与内质网驻留STING在高尔基体的积累。鉴于已知的作用的外被体蛋白复合物I，我们推测，COPA功能的丧失导致增强I型IFN信号转导由于高尔基体到ER STING检索失败。这些数据突出了ER-高尔基体轴在控制自身炎症中的重要性，并为COPA综合征的治疗策略提供了信息。
Heterozygous missense mutations in COPA underlie constitutive interferon signaling through STING, thereby defining a novel type I interferonopathy and emphasizing the importance of the ER–Golgi axis in interferon homeostasis. Based on these results, three patients have been treated with interferon signaling (JAK1) inhibitors. Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER–Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.
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