Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C.
Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C.
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DOI：
10.1038/s41586-021-03762-2
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发表时间：
2021-08
期刊：
影响因子：
64.8
通讯作者：
Yan N
中科院分区：
文献类型：
--
作者：
Chu TT;Tu X;Yang K;Wu J;Repa JJ;Yan N
STING激活的经典模式是通过结合由DNA传感器环GMP-AMP合酶（cGAS）产生的环二核苷酸2 '3'-环GMP-AMP（cGAMP），其对于针对微生物感染和自身免疫性疾病的先天免疫应答是重要的。独立于cGAS的STING激活模式还不太清楚。在这里，通过时空分辨的邻近标记筛选，然后进行定量蛋白质组学，我们确定了溶酶体膜蛋白尼曼-匹克C1型（NPC 1）作为辅助因子在STING的贩运。NPC 1与STING相互作用，并将其招募到溶酶体中，以便在人和小鼠细胞中降解。值得注意的是，我们发现敲除Npc 1通过物理连接或“拴系”STING到SREBP 2运输来“引发”STING信号传导。NPC 1蛋白的丢失也通过阻断溶酶体降解“增强”STING信号传导。STING信号的引发和加强都是Npc 1 −/−小鼠严重神经系统疾病所必需的。Sting 1（编码STING的基因）或Irf 3的基因缺失，而不是Cgas的基因缺失，显着减少了小胶质细胞的激活，减轻了Npc 1 −/−小鼠小脑中浦肯野神经元的丢失，从而改善了运动功能。我们的研究确定了影响神经病理学的STING激活的cGAS和cGAMP独立模式，并为C型尼曼-皮克病的治疗提供了治疗靶点。
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.
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影响因子：
14.8
作者：
Hung V;Udeshi ND;Lam SS;Loh KH;Cox KJ;Pedram K;Carr SA;Ting AY
通讯作者：
Ting AY
影响因子：
2.5
作者：
Shin, Samuel D.;Shin, Alexandra;Soriano, Salvador
通讯作者：
Soriano, Salvador
DOI：
10.1038/s41577-021-00524-z
发表时间：
2021-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Decout A;Katz JD;Venkatraman S;Ablasser A
通讯作者：
Ablasser A
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8.8
作者：
Gonugunta VK;Sakai T;Pokatayev V;Yang K;Wu J;Dobbs N;Yan N
通讯作者：
Yan N