一种非核苷酸激动剂,能与 STING 的半胱氨酸残基共价结合。

IF 2 4区 生物学 Q4 CELL BIOLOGY
Cell structure and function Pub Date : 2023-02-16 Epub Date: 2022-12-28 DOI:10.1247/csf.22085
Kentaro Matsumoto, Shenwei Ni, Hiroyuki Arai, Takashi Toyama, Yoshiro Saito, Takehiro Suzuki, Naoshi Dohmae, Kojiro Mukai, Tomohiko Taguchi
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引用次数: 0

摘要

干扰素基因刺激因子(STING)是一种内质网定位的跨膜蛋白,是2',3'-环鸟苷单磷酸腺苷单磷酸(cGAMP)的受体,cGAMP合成酶(cGAS)是胞质双链DNA传感器产生的第二信使。cGAS-STING通路通过诱导I型干扰素在多种DNA病原体感染的先天免疫应答中发挥关键作用。STING的药理激活是一种很有前景的癌症治疗策略,因此开发强效和选择性的STING激动剂一直是人们追求的目标。本文报道了小鼠STING可被氧化苯larsin (PAO)激活,PAO是一种可渗透膜的三价砷化合物,优先与半胱氨酸残基(Cys)的巯基反应。PAO激活STING不需要cGAS或cGAMP。通过质谱分析胰蛋白酶和胰凝乳酶消化STING产生的肽,鉴定出几种PAO加合物,表明PAO与STING共价结合。筛选具有单个Cys到丝氨酸残基(Ser)的STING变体表明,Cys88和Cys291对PAO应答至关重要。与cGAMP一样,PAO激活STING需要er到高尔基体的传递和STING的棕榈酰化。我们的研究结果确定了一种不靶向cgamp结合口袋的非核苷酸STING激动剂,并证明STING的Cys可以成为开发STING激动剂的新靶点。关键词:STING激动剂,半胱氨酸修饰,先天免疫,氧化苯larsin
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A non-nucleotide agonist that binds covalently to cysteine residues of STING.

Stimulator of interferon genes (STING) is an ER-localized transmembrane protein and the receptor for 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which is a second messenger produced by cGAMP synthase (cGAS), a cytosolic double-stranded DNA sensor. The cGAS-STING pathway plays a critical role in the innate immune response to infection of a variety of DNA pathogens through the induction of the type I interferons. Pharmacological activation of STING is a promising therapeutic strategy for cancer, thus the development of potent and selective STING agonists has been pursued. Here we report that mouse STING can be activated by phenylarsine oxide (PAO), a membrane permeable trivalent arsenic compound that preferentially reacts with thiol group of cysteine residue (Cys). The activation of STING with PAO does not require cGAS or cGAMP. Mass spectrometric analysis of the peptides generated by trypsin and chymotrypsin digestion of STING identifies several PAO adducts, suggesting that PAO covalently binds to STING. Screening of STING variants with single Cys to serine residues (Ser) reveals that Cys88 and Cys291 are critical to the response to PAO. STING activation with PAO, as with cGAMP, requires the ER-to-Golgi traffic and palmitoylation of STING. Our results identify a non-nucleotide STING agonist that does not target the cGAMP-binding pocket, and demonstrate that Cys of STING can be a novel target for the development of STING agonist.Key words: STING agonist, cysteine modification, innate immunity, phenylarsine oxide.

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来源期刊
Cell structure and function
Cell structure and function 生物-细胞生物学
CiteScore
2.50
自引率
0.00%
发文量
6
审稿时长
>12 weeks
期刊介绍: Cell Structure and Function is a fully peer-reviewed, fully Open Access journal. As the official English-language journal of the Japan Society for Cell Biology, it is published continuously online and biannually in print. Cell Structure and Function publishes important, original contributions in all areas of molecular and cell biology. The journal welcomes the submission of manuscripts on research areas such as the cell nucleus, chromosomes, and gene expression; the cytoskeleton and cell motility; cell adhesion and the extracellular matrix; cell growth, differentiation and death; signal transduction; the protein life cycle; membrane traffic; and organelles.
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