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Using PET imaging to track STING-induced interferon signaling [Medical Sciences]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2021-09-21 , DOI: 10.1073/pnas.2114839118
Enitome E Bafor 1 , Howard A Young 1
Affiliation  

In the 19th century, Ilya Metchnikoff defined and broadened our initial understanding of phagocytosis and, in 1908, went on to show that a cellular component (i.e., DNA) stimulates immune responses (1). About a century later, Janeway conceptualized pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs) (2). Since then, we know that PAMP recognition by innate immune cells via PRRs activates the production of several cytokines, including interferons (IFNs), with the eventual recruitment of lymphocytes. Subsequent research discovered that innate immune recognition of double-stranded DNA (dsDNA) triggers autoimmune diseases (3). However, before the discovery of dsDNA sensors, an endoplasmic reticulum (ER) protein encoded by the TMEM173 gene, known as a stimulator of IFN genes (STING), was identified as a significant factor involving DNA recognition in innate immunity (4). Subsequently, scientists discovered that the direct cytosolic DNA sensor (cGAS) activates the expression of type 1 IFNs (5). Today, it is well known that activation of cGAS-cGAMP-STING signaling is triggered by cytosolic DNA and is necessary for antimicrobial and antitumor immune responses. In PNAS, Liang et al. (6) describe an innovative process for monitoring STING-induced IFN signaling. Induction of IFN signaling by STING occurs on detection of cytoplasmic DNA, which may be tumor- or microbial-derived. STING is activated when cGAS catalyzes the synthesis of cyclic dinucleotides (CDNs) including 2′3′-cGAMP (7). STING is translocated from the ER to the perinucleus, phosphorylated by TANK-binding kinase 1 (TBK1) and recruits IFN regulatory factor 3 (IRF3), which in turn is phosphorylated by TBK1, forms a dimer, and enters the nucleus. Phosphorylated IRF3 activates transcription of type 1 IFNs and other relevant cytokines (8) which bind to the heterodimeric IFN receptors (IFNAR1 and IFNAR2) and recruits Janus family kinase 1(Jak1) and tyrosine kinase 2 (Tyk2), which in turn phosphorylates and activates IFNAR1 and IFNAR2. …

中文翻译:

使用 PET 成像跟踪 STING 诱导的干扰素信号传导 [医学]

在 19 世纪,Ilya Metchnikoff 定义并拓宽了我们对吞噬作用的初步理解,并在 1908 年继续表明细胞成分(即 DNA)可刺激免疫反应 ( 1 )。大约一个世纪后,Janeway 概念化了模式识别受体 (PRR) 和病原体相关分子模式 (PAMP) ( 2 )。从那时起,我们知道先天免疫细胞通过 PRR 识别 PAMP 会激活几种细胞因子的产生,包括干扰素 (IFN),最终募集淋巴细胞。随后的研究发现,双链 DNA (dsDNA) 的先天免疫识别会引发自身免疫性疾病 ( 3 )。然而,在发现 dsDNA 传感器之前,由TMEM173基因被称为 IFN 基因 (STING) 的刺激物,被确定为涉及先天免疫中 DNA 识别的重要因素 ( 4 )。随后,科学家发现直接胞质 DNA 传感器 (cGAS) 可激活 1 型 IFN 的表达 ( 5 )。今天,众所周知,cGAS-cGAMP-STING 信号的激活是由细胞质 DNA 触发的,并且是抗菌和抗肿瘤免疫反应所必需的。在 PNAS 中,Liang 等人。( 6) 描述了一种监测 STING 诱导的 IFN 信号的创新过程。STING 对 IFN 信号传导的诱导发生在检测细胞质 DNA 时,该细胞质 DNA 可能来自肿瘤或微生物。当 cGAS 催化包括 2'3'-cGAMP 在内的环状二核苷酸 (CDN) 的合成时,STING 被激活 ( 7 )。STING 从 ER 转移到核周,被 TANK 结合激酶 1 (TBK1) 磷酸化并募集 IFN 调节因子 3 (IRF3),后者又被 TBK1 磷酸化,形成二聚体并进入细胞核。磷酸化 IRF3 激活 1 型 IFN 和其他相关细胞因子的转录(8)结合异二聚体 IFN 受体(IFNAR1 和 IFNAR2)并募集 Janus 家族激酶 1(Jak1)和酪氨酸激酶 2(Tyk2),进而磷酸化并激活 IFNAR1 和 IFNAR2。…
更新日期:2021-09-15
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