Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Traffic. 2023 Dec;24(12):576-586. doi: 10.1111/tra.12918. Epub 2023 Sep 2.
To combat microbial infections, mammalian cells use a variety of innate immune response pathways to induce synthesis of anti-microbial proteins. The cGAS/STING pathway recognizes cytoplasmic viral or cellular DNA to elicit signals that lead to type I interferon and other cytokine synthesis. cGAMP, synthesized by DNA-activated cGAS, activates the ER-associated protein, STING, which oligomerizes and translocates to other intracellular membrane compartments to trigger different branches of signaling. We have reported that, in the ER, EGFR-mediated phosphorylation of Tyr245 of STING is required for its transit to the late endosomes, where it recruits and activates the transcription factor IRF3 required for IFN induction. In the current study, we inquired whether STING Tyr245 phosphorylation per se or STING's location in the late endosomes was critical for its ability to recruit IRF3 and induce IFN. Using pharmacological inhibitors or genetic ablation of proteins that are essential for specific steps of STING trafficking, we demonstrated that the presence of STING in the late endosomal membranes, even without Tyr245 phosphorylation, was sufficient for IRF3-mediated IFN induction.
为了对抗微生物感染，哺乳动物细胞利用多种先天免疫反应途径诱导抗微生物蛋白的合成。cGAS/STING 途径识别细胞质中的病毒或细胞 DNA，引发导致 I 型干扰素和其他细胞因子合成的信号。cGAMP 由 DNA 激活的 cGAS 合成，激活 ER 相关蛋白 STING，后者寡聚化并转移到其他细胞内膜区室，触发不同的信号转导分支。我们已经报道，在 ER 中，EGFR 介导的 STING 酪氨酸 245 的磷酸化是其向晚期内体易位所必需的，在晚期内体中，它募集并激活 IFN 诱导所需的转录因子 IRF3。在本研究中，我们探究了 STING 酪氨酸 245 磷酸化本身或 STING 在晚期内体中的位置是否对其招募 IRF3 和诱导 IFN 的能力至关重要。使用药理学抑制剂或对 STING 运输特定步骤必不可少的蛋白质进行基因敲除，我们证明了晚期内体膜中 STING 的存在，即使没有 Tyr245 磷酸化，也足以介导 IRF3 介导的 IFN 诱导。
