TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages
TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages
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DOI：
10.1073/pnas.1901090116
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发表时间：
2019-08-13
影响因子：
11.1
通讯作者：
Kiss-Toth, Endre
中科院分区：
文献类型：
--
作者：
Li, Yang;James, Sharmy J.;Kiss-Toth, Endre
IFN信号的调节在宿主对病原体的识别和应答中至关重要，而其失调是多种慢性疾病的发病机制的基础。干扰素基因刺激因子（STING）是干扰素诱导天然免疫途径的重要介导因子，但其直接辅助调节因子的研究却很少。我们在这里报告，TMEM 203，一个保守的推定的跨膜蛋白，是一个细胞内调节STING介导的信号。我们表明，TMEM 203相互作用，功能合作，并与STING细胞刺激后，这反过来又导致激酶TBK 1的激活，和IRF 3转录因子共迁移。这会诱导巨噬细胞中的靶基因，包括IFN-β。使用Tmem 203敲除骨髓衍生的巨噬细胞和人单核细胞衍生的巨噬细胞中TMEM 203的瞬时敲低，我们表明TMEM 203蛋白是cGAMP诱导的STING活化所需的。与STING不同，TMEM 203 mRNA水平在来自系统性红斑狼疮患者的T细胞中升高，系统性红斑狼疮是一种以I型干扰素过表达为特征的疾病。此外，TMEM 203 mRNA水平与疾病活动性相关，如通过补体蛋白C3的血清水平所评估的。TMEM 203的鉴定揭示了STING介导的先天免疫反应的控制，为STING相关炎症性疾病的治疗干预提供了潜在的新机制。
Regulation of IFN signaling is critical in host recognition and response to pathogens while its dysregulation underlies the pathogenesis of several chronic diseases. STimulator of IFN Genes ( STING) has been identified as a critical mediator of IFN inducing innate immune pathways, but little is known about direct coregulators of this protein. We report here that TMEM203, a conserved putative transmembrane protein, is an intracellular regulator of STING-mediated signaling. We show that TMEM203 interacts, functionally cooperates, and comigrates with STING following cell stimulation, which in turn leads to the activation of the kinase TBK1, and the IRF3 transcription factor. This induces target genes in macrophages, including IFN-beta. Using Tmem203 knockout bone marrow-derived macrophages and transient knockdown of TMEM203 in human monocyte-derived macrophages, we show that TMEM203 protein is required for cGAMP-induced STING activation. Unlike STING, TMEM203 mRNA levels are elevated in T cells from patients with systemic lupus erythematosus, a disease characterized by the overexpression of type I interferons. Moreover, TMEM203 mRNA levels are associated with disease activity, as assessed by serum levels of the complement protein C3. Identification of TMEM203 sheds light into the control of STING-mediated innate immune responses, providing a potential novel mechanism for therapeutic interventions in STING-associated inflammatory diseases.