Interruption of post-Golgi STING trafficking activates tonic interferon signaling.
Interruption of post-Golgi STING trafficking activates tonic interferon signaling.
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DOI：
10.1038/s41467-022-33765-0
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发表时间：
2022-11-15
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
cGAS-STING途径的激活传统上被认为是一种“干扰素释放”机制，其中微生物DNA或环状二核苷酸的检测引发I型干扰素应答。该途径是否可以在没有致病性配体暴露的情况下被激活还不太清楚。在这里，我们表明，高尔基体到溶酶体STING辅因子的损失，但不是ER到高尔基体辅因子，选择性激活紧张性干扰素信号。后高尔基体运输的损害延长了STING高尔基体停留时间，导致免疫信号传导和抗感染保护的提高。从机制上讲，反式高尔基体卷曲螺旋蛋白GCC 2和几种RAB GTP酶作为STING后高尔基体运输的关键调节因子。这些因子的基因组缺失有效地激活cGAS-STING信号传导，而不引发cGAS的任何致病性触发。Gcc 2 −/−小鼠产生STING依赖性血清学自身免疫。Gcc 2缺失或Rab 14缺失的癌细胞诱导T细胞和IFN依赖性抗肿瘤免疫并抑制小鼠肿瘤生长。总之，我们提出了一个“基础流量”的紧张cGAS-STING信号传导机制，调节后高尔基体STING贩运的水平，这可以用于癌症免疫治疗。微生物DNA被cGAS-STING途径识别，这导致I型干扰素应答。在这里，作者表明干扰素激活的基础通量也可以通过干扰STING从高尔基体运输到溶酶体来触发。
Activation of the cGAS-STING pathway is traditionally considered a “trigger-release” mechanism where detection of microbial DNA or cyclic di-nucleotides sets off the type I interferon response. Whether this pathway can be activated without pathogenic ligand exposure is less well understood. Here we show that loss of Golgi-to-lysosome STING cofactors, but not ER-to-Golgi cofactors, selectively activates tonic interferon signalling. Impairment of post-Golgi trafficking extends STING Golgi-dwell time, resulting in elevated immune signalling and protection against infection. Mechanistically, trans-Golgi coiled coil protein GCC2 and several RAB GTPases act as key regulators of STING post-Golgi trafficking. Genomic deletion of these factors potently activates cGAS-STING signalling without instigating any pathogenic trigger for cGAS. Gcc2−/− mice develop STING-dependent serologic autoimmunity. Gcc2-deleted or Rab14-deleted cancer cells induce T-cell and IFN-dependent anti-tumour immunity and inhibit tumour growth in mice. In summary, we present a “basal flux” mechanism for tonic cGAS-STING signalling, regulated at the level of post-Golgi STING trafficking, which could be exploited for cancer immunotherapy. Microbial DNA is recognized by the cGAS-STING pathway, which leads to a type I interferon response. Here authors show that a basal flux of interferon activation could also be triggered by interference with STING trafficking from the Golgi apparatus to the lysosomes.
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影响因子：
64.8
作者：
通讯作者：
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DOI：
10.1056/nejmoa1312625
发表时间：
2014-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Liu Y;Jesus AA;Marrero B;Yang D;Ramsey SE;Sanchez GAM;Tenbrock K;Wittkowski H;Jones OY;Kuehn HS;Lee CR;DiMattia MA;Cowen EW;Gonzalez B;Palmer I;DiGiovanna JJ;Biancotto A;Kim H;Tsai WL;Trier AM;Huang Y;Stone DL;Hill S;Kim HJ;St Hilaire C;Gurprasad S;Plass N;Chapelle D;Horkayne-Szakaly I;Foell D;Barysenka A;Candotti F;Holland SM;Hughes JD;Mehmet H;Issekutz AC;Raffeld M;McElwee J;Fontana JR;Minniti CP;Moir S;Kastner DL;Gadina M;Steven AC;Wingfield PT;Brooks SR;Rosenzweig SD;Fleisher TA;Deng Z;Boehm M;Paller AS;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
影响因子：
64.8
作者：
Chu TT;Tu X;Yang K;Wu J;Repa JJ;Yan N
通讯作者：
Yan N
影响因子：
16.6
作者：
Mukai K;Ogawa E;Uematsu R;Kuchitsu Y;Kiku F;Uemura T;Waguri S;Suzuki T;Dohmae N;Arai H;Shum AK;Taguchi T
通讯作者：
Taguchi T
DOI：
10.1126/science.1244040
发表时间：
2013-09-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li XD;Wu J;Gao D;Wang H;Sun L;Chen ZJ
通讯作者：
Chen ZJ