Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation.
Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation.
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Tau通过PQBP 1-cGAS-STING途径激活小胶质细胞以促进脑炎症。
DOI：
10.1038/s41467-021-26851-2
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发表时间：
2021-11-15
影响因子：
16.6
通讯作者：
Okazawa H
中科院分区：
文献类型：
--
作者：
Jin M;Shiwaku H;Tanaka H;Obita T;Ohuchi S;Yoshioka Y;Jin X;Kondo K;Fujita K;Homma H;Nakajima K;Mizuguchi M;Okazawa H
脑部炎症通常伴随着并加速神经退行性变。在这里，我们报道了一个小胶质机制，其中聚谷氨酰胺结合蛋白1 （PQBP1）通过直接相互作用感知外源性tau 3R/4R蛋白，并通过激活环GMP-AMP合成酶(cGAS)-干扰素基因刺激因子（STING）途径触发先天免疫反应。他莫昔芬诱导的PQBP1在体外原代培养和小鼠脑内小胶质细胞特异性缺失表明，PQBP1是传感tau诱导核因子κB （NFκB）核易位、NFκB依赖性炎症基因转录、体内脑炎症以及最终小鼠认知障碍的关键。总的来说，PQBP1不仅是人类免疫缺陷病毒（HIV） cDNA的cGAS-STING通路中的细胞内受体，也是传染性神经退行性疾病蛋白tau的细胞内受体。这项研究描述了病毒感染和神经退行性疾病中常见的脑炎症机制。脑部炎症通常会加速神经退行性变，但其机制尚未完全确定。本文作者表明，小胶质细胞中的PQBP1对于感知外源性Tau 3r / 4r蛋白很重要，并通过cGAS和STING触发先天免疫反应，导致认知障碍。
Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders. Brain inflammation generally accelerates neurodegeneration but the mechanisms of this are not fully characterised. Here the authors show that PQBP1 in microglia is important for sensing extrinsic Tau 3 R/4 R proteins and triggers an innate immune response through cGAS and STING resulting in cognitive impairment.
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影响因子：
3.7
作者：
Brabazon F;Bermudez S;Shaughness M;Khayrullina G;Byrnes KR
通讯作者：
Byrnes KR
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
16.6
作者：
He, Yang;Li, Bin;Mao, Scott X.
通讯作者：
Mao, Scott X.
影响因子：
15.1
作者：
Bemiller SM;McCray TJ;Allan K;Formica SV;Xu G;Wilson G;Kokiko-Cochran ON;Crish SD;Lasagna-Reeves CA;Ransohoff RM;Landreth GE;Lamb BT
通讯作者：
Lamb BT
影响因子：
25
作者：
Asai H;Ikezu S;Tsunoda S;Medalla M;Luebke J;Haydar T;Wolozin B;Butovsky O;Kügler S;Ikezu T
通讯作者：
Ikezu T