小柯机器人

STING信号介导C型尼曼-皮克病的发生
2021-07-25 14:03

美国德克萨斯大学Nan Yan研究小组发现,STING信号介导C型尼曼-皮克病的发生。相关论文于2021年7月21日在线发表在《自然》杂志上。

研究人员表示,STING激活的经典模式是通过结合环状二核苷酸2′3′-环状GMP-AMP(cGAMP),由DNA传感器环状GMP-AMP合成酶(cGAS)产生,这对微生物感染和自身免疫性疾病的先天免疫反应很重要。对不依赖cGAS的STING激活方式则了解甚少。

通过时空分辨的临近标记筛选和定量蛋白质组学,研究人员发现溶酶体膜蛋白Niemann-Pick C1(NPC1)是STING转运的一个辅助因子。在人类和小鼠细胞中,NPC1与STING相互作用并将其招募到溶酶体中进行降解。

值得注意的是,研究人员发现NPC1的敲除通过物理连接或“拴住”STING与SREBP2的转运来“激励”STING信号。NPC1蛋白的缺失也通过阻断溶酶体的降解来“促进”STING信号的传递。在Npc1-/-小鼠中,STING信号的启动和增强对严重的神经系统疾病都是必需的。Sting1(编码STING的基因)或Irf3的基因缺失,而不是Cgas的基因缺失,可显著减少小胶质细胞的激活,缓解Npc1-/-小脑中浦肯野神经元的丢失,从而改善运动功能。

这项研究确定了一种与cGAS和cGAMP无关的STING激活模式,它影响了神经病理学,并为治疗C型尼曼-皮克病提供了一个治疗靶标。

附:英文原文

Title: Tonic prime-boost of STING signalling mediates Niemann–Pick disease type C

Author: Ting-Ting Chu, Xintao Tu, Kun Yang, Jianjun Wu, Joyce J. Repa, Nan Yan

Issue&Volume: 2021-07-21

Abstract: The classic mode of STING activation is through binding the cyclic dinucleotide 2′3′-cyclic GMP–AMP (cGAMP), produced by the DNA sensor cyclic GMP–AMP synthase (cGAS), which is important for the innate immune response to microbial infection and autoimmune disease. Modes of STING activation that are independent of cGAS are much less well understood. Here, through a spatiotemporally resolved proximity labelling screen followed by quantitative proteomics, we identify the lysosomal membrane protein Niemann–Pick type C1 (NPC1) as a cofactor in the trafficking of STING. NPC1 interacts with STING and recruits it to the lysosome for degradation in both human and mouse cells. Notably, we find that knockout of Npc1 ‘primes’ STING signalling by physically linking or ‘tethering’ STING to SREBP2 trafficking. Loss of NPC1 protein also ‘boosts’ STING signalling by blocking lysosomal degradation. Both priming and boosting of STING signalling are required for severe neurological disease in the Npc1/ mouse. Genetic deletion of Sting1 (the gene that encodes STING) or Irf3, but not that of Cgas, significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1/ mice, leading to improved motor function. Our study identifies a cGAS- and cGAMP-independent mode of STING activation that affects neuropathology and provides a therapeutic target for the treatment of Niemann–Pick disease type C.

DOI: 10.1038/s41586-021-03762-2

Source: https://www.nature.com/articles/s41586-021-03762-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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