STING介导的宿主免疫反应诱导
中文名称
通路描述
STING（干扰素基因刺激因子；也称为MITA/ERIS/MPYS/TMEM173）是内质网（ER）驻留蛋白，对响应核酸的有效I型干扰素产生至关重要。确实，已证明选择性的病原体来源DNA或RNA可激活人类和小鼠细胞中的STING（Ishikawa H和Barber GN 2008; Ishikawa H等。2009; Sun W等。2009; Prantner D等。2010）。重要的是，体外研究表明，STING对于结核分枝杆菌（Manzanillo PS等。2012）、裂殖疟原虫（Sharma S等。2011）和人类免疫缺陷病毒（HIV）诱导的I型干扰素产生是必需的 [Yan N等。2010]。结核分枝杆菌、裂殖疟原虫和HIV是全球每年杀死数百万人的三种最致命的病原体。STING还涉及由病毒和靶细胞膜融合引起的I型干扰素反应，该反应独立于DNA、RNA和病毒衣壳 [Holm CK等。2012]。在稳态条件下，STING定位于ER膜中的转位子复合物。然而，当受到细胞内DNA刺激时，它通过机制（尚不清楚）从ER转运到细胞质囊泡（通过高尔基体）（Ishikawa H和Barber GN 2008; Sun W等。2009; Ishikawa H等。2009; Saitoh T等。2009）。小鼠 Sting在dsDNA刺激的胚胎成纤维细胞（MEF）细胞中的 trafficking 依赖于与自噬相关基因9a（Atg9a）（Saitoh T等。2009）。据报道，STING作为响应细胞内dsDNA的信号转导适配器或核心受体发挥作用（Unterholzner L等。2010; Zhang Z等。2011）。STING也被证明作为直接DNA传感器，诱导人类端粒酶纤维母细胞（hTERT-BJ1）和小鼠胚胎成纤维细胞（MEFs）的原发性免疫反应（Abe T等。2013）。此外，STING被认为作为环二核苷酸的直接传感器发挥作用。STING已被证明直接与人类胚胎肾HEK293T细胞裂解物中的c-di-GMP直接相互作用（Burdette DL等。2011）。一旦STING受到刺激，其C端作为信号支架招募IRF3和TBK1，导致TBK1依赖性磷酸化IRF3（Tanaka Y和Chen ZJ 2012）。小鼠STING可结合血管破坏剂5,6-二甲基Xanthone-4-乙酸（DMXAA）和抗病毒小分子10-羧甲基-9-蒽酮（CMA），以诱导I型干扰素产生，表明STING介导的宿主反应存在物种特异性药物效应（Conlon J等。2013; Cavlar T等。2013）。
英文描述
STING mediated induction of host immune responses STING (stimulator of IFN genes; also known as MITA/ERIS/MPYS/TMEM173) is an endoplasmic reticulum (ER) resident, which is required for effective type I IFN production in response to nucleic acids. Indeed, select pathogen-derived DNA or RNA were shown to activate STING in human and mouse cells (Ishikawa H and Barber GN 2008; Ishikawa H et al. 2009; Sun W et al. 2009; Prantner D et al. 2010). Importantly, in vitro studies have shown that STING is essential for Mycobacterium tuberculosis (Manzanillo PS et al. 2012), Plasmodium falciparum (Sharma S et al. 2011) and human immunodeficiency virus (HIV) induced type I IFN production [Yan N et al 2010]. Mycobacterium tuberculosis, plasmodium falciparum and HIV are three deadliest pathogens, which kill millions of people each year worldwide.STING has been also implicated in type I IFN response which was stimulated by fusion of viral and target-cell membrane in a manner independent of DNA, RNA and viral capsid [Holm CK et al 2012].Under steady state conditions, STING is positioned at the translocon complex within the ER membrane. However upon stimulation with intracellular DNA it translocates from ER to perinuclear vesicles via the Golgi by mechanisms that remain unclear (Ishikawa H and Barber GN 2008; Sun W et al. 2009; Ishikawa H et al. 2009; Saitoh T et al. 2009). Mouse Sting trafficking in dsDNA-stimulated mouse embryonic fibroblasts (MEF) cells was found to depend on autophagy-related gene 9a (Atg9a) (Saitoh T et al. 2009).STING was reported to function as a signaling adaptor or coreceptor in response to cytosolic dsDNA (Unterholzner L et al. 2010; Zhang Z et al. 2011). STING was also shown to function as a direct DNA sensor to induce the innate immune response in human telomerase fibroblasts (hTERT-BJ1) and murine embryonic fibroblasts (MEFs) (Abe T et al. 2013). Additionally, STING is thought to function as a direct sensor of cyclic dinucleotides. STING was shown to interact directly with c-di-GMP in human embryonic kidney HEK293T cell lysates (Burdette DL et al. 2011). Once STING is stimulated, its C-terminus serves as a signaling scaffold to recruit IRF3 and TBK1, which leads to TBK1-dependent phosphorylation of IRF3 (Tanaka Y and Chen ZJ 2012).Mouse, but not human STING, can also bind vascular disrupting agents 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and the antiviral small molecule 10-carboxymethyl-9-acridanone (CMA) to induce type I IFN production, suggesting a species-specific drug effect on the STING-mediated host response (Conlon J et al. 2013; Cavlar T et al. 2013).
所含基因
5 个基因