Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
AMED-PRIME, Japan Agency for Medical Research and Development, Tokyo, Japan.
Front Immunol. 2021 May 3;12:646304. doi: 10.3389/fimmu.2021.646304. eCollection 2021.
DNA is present in the nucleus and mitochondria of eukaryotic cells. There are, however, certain instances in which DNA emerges in the cytosol. The two major sources of cytosolic DNA are self DNA that is leaked out from the nucleus or mitochondria, and non-self DNA from DNA viruses. The cytosolic DNA triggers the host immune response. Recent studies have identified two key molecules, cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) in this immune response. STING is an endoplasmic reticulum (ER) protein. After STING binding to cGAMP, STING exits the ER and translocates to the Golgi, where STING triggers the type I interferon- and proinflammatory responses through the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB). STING also activates other cellular responses including cell senescence, autophagy, and cell death. In this review, we focus on emerging issues regarding the regulation of STING by membrane traffic, with a particular focus on the retrograde membrane traffic from the Golgi to the ER. The retrograde membrane traffic is recently shown by us and others to be critical for silencing the STING signaling pathway and the defect in this traffic underlies the pathogenesis of the COPA syndrome, a monogenic autoinflammatory disease caused by missense mutations of coatomer protein complex subunit α (COP-α).
DNA 存在于真核细胞的细胞核和线粒体中。然而，在某些情况下，DNA 也会出现在细胞质中。细胞质 DNA 的两个主要来源是从细胞核或线粒体泄漏出来的自身 DNA，以及来自 DNA 病毒的非自身 DNA。细胞质 DNA 会引发宿主的免疫反应。最近的研究在这种免疫反应中鉴定出了两个关键分子，环鸟苷酸-腺苷酸（cGAMP）合酶（cGAS）和干扰素基因刺激因子（STING）。STING 是内质网（ER）蛋白。STING 与 cGAMP 结合后，从 ER 中逸出并转运到高尔基体，在那里 STING 通过激活干扰素调节因子 3（IRF3）和核因子-κB（NF-κB）来触发 I 型干扰素和炎症反应。STING 还激活其他细胞反应，包括细胞衰老、自噬和细胞死亡。在这篇综述中，我们重点关注膜运输对 STING 调节的新问题，特别关注从高尔基体到内质网的逆行膜运输。最近我们和其他人的研究表明，逆行膜运输对于沉默 STING 信号通路至关重要，而这种运输的缺陷是 COPA 综合征（一种由衣壳蛋白复合物亚单位 α（COP-α）错义突变引起的单基因自身炎症性疾病）发病机制的基础。
