Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling.
Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling.
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DOI：
10.1016/j.cell.2013.09.049
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发表时间：
2013-10-24
期刊：
影响因子：
64.5
通讯作者：
Barber GN
中科院分区：
文献类型：
--
作者：
Konno H;Konno K;Barber GN
通过微生物或自身DNA以及环状二核苷酸（CDN）激活STING（干扰素基因刺激因子）途径导致诱导抑制病原体复制并促进适应性免疫的许多基因。然而，持续的基因转录被严格阻止，以避免致命的STING依赖性促炎性疾病的机制仍然未知。我们在此证明，在自噬依赖性STING将TBK 1（TANK结合激酶1）递送至内体/溶酶体区室并激活转录因子IRF 3（干扰素调节因子3）和NF-κB（核因子κ β）后，STING随后被丝氨酸/苏氨酸β-51样激酶（ULK 1/ATG 1）磷酸化，IRF 3功能受到抑制。ULK 1活化发生在与其阻遏物腺嘌呤一磷酸活化蛋白激酶（AMPK）解离后，并且由cGAMP合酶cGAS产生的CDN引起。因此，虽然CDN最初可以促进STING功能，但它们随后触发STING活性的负反馈控制，从而防止先天免疫基因的持续转录。
Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’s generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes.
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影响因子：
32.4
作者：
Gall A;Treuting P;Elkon KB;Loo YM;Gale M Jr;Barber GN;Stetson DB
通讯作者：
Stetson DB
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8.8
作者：
Kranzusch PJ;Lee AS;Berger JM;Doudna JA
通讯作者：
Doudna JA
影响因子：
32.4
作者：
Henault J;Martinez J;Riggs JM;Tian J;Mehta P;Clarke L;Sasai M;Latz E;Brinkmann MM;Iwasaki A;Coyle AJ;Kolbeck R;Green DR;Sanjuan MA
通讯作者：
Sanjuan MA
DOI：
10.1073/pnas.1215006109
发表时间：
2012-11-20
影响因子：
11.1
作者：
Ahn, Jeonghyun;Gutman, Delia;Barber, Glen N.
通讯作者：
Barber, Glen N.