Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage.
Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage.
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ATM 和 IFI16 对 DNA 传感适配器 STING 的非规范激活可在核 DNA 损伤后介导 NF-κB 信号转导。
DOI：
10.1016/j.molcel.2018.07.034
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发表时间：
2018-09-06
期刊：
影响因子：
16
通讯作者：
Unterholzner L
中科院分区：
文献类型：
--
作者：
Dunphy G;Flannery SM;Almine JF;Connolly DJ;Paulus C;Jønsson KL;Jakobsen MR;Nevels MM;Bowie AG;Unterholzner L
DNA损伤可以被先天免疫系统感知为与DNA相关的分子模式。在这里，我们发现角质形成细胞和其他人类细胞在依托泊苷诱导的DNA损伤的数小时内产生先天免疫应答，这涉及DNA传感适配器STING，但不依赖于胞质DNA受体cGAS。STING的这种非典型激活由DNA结合蛋白IFI 16以及DNA损伤反应因子ATM和PARP-1介导，导致包括肿瘤抑制因子p53和E3泛素连接酶TRAF 6的替代STING信号传导复合物的组装。TRAF 6催化STING上K63连接的泛素链的形成，导致转录因子NF-κB的活化和替代STING依赖性基因表达程序的诱导。我们建议STING作为一个信号中枢，根据其激活模式协调转录反应。依托泊苷诱导的核DNA损伤导致先天免疫应答ATM和IFI 16可以以不依赖于cGAS的方式激活STING非经典STING信号传导主要激活NF-κB，而不是IRF 3。这涉及STING上TRAF 6介导的K63连接的泛素链的组装。Dunphy等人表明ATM检测到依托泊苷诱导的损伤会导致DNA传感衔接子STING的非典型激活。这导致替代STING信号传导复合物的组装和NF-κ B依赖性转录程序的诱导。
DNA damage can be sensed as a danger-associated molecular pattern by the innate immune system. Here we find that keratinocytes and other human cells mount an innate immune response within hours of etoposide-induced DNA damage, which involves the DNA sensing adaptor STING but is independent of the cytosolic DNA receptor cGAS. This non-canonical activation of STING is mediated by the DNA binding protein IFI16, together with the DNA damage response factors ATM and PARP-1, resulting in the assembly of an alternative STING signaling complex that includes the tumor suppressor p53 and the E3 ubiquitin ligase TRAF6. TRAF6 catalyzes the formation of K63-linked ubiquitin chains on STING, leading to the activation of the transcription factor NF-κB and the induction of an alternative STING-dependent gene expression program. We propose that STING acts as a signaling hub that coordinates a transcriptional response depending on its mode of activation. Etoposide-induced nuclear DNA damage causes an innate immune response ATM and IFI16 can activate STING in a cGAS-independent manner Non-canonical STING signaling predominantly activates NF-κB, rather than IRF3 This involves the TRAF6-mediated assembly of K63-linked ubiquitin chains on STING DNA damage can activate an innate immune response. Dunphy et al. show that the detection of etoposide-induced damage by ATM causes the non-canonical activation of the DNA sensing adaptor STING. This results in the assembly of an alternative STING signaling complex and the induction of an NF-κB-dependent transcriptional program.
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影响因子：
4.8
作者：
Clark, Kristopher;Plater, Lorna;Cohen, Philip
通讯作者：
Cohen, Philip
影响因子：
21.3
作者：
Glück S;Guey B;Gulen MF;Wolter K;Kang TW;Schmacke NA;Bridgeman A;Rehwinkel J;Zender L;Ablasser A
通讯作者：
Ablasser A
影响因子：
6.7
作者：
Harwardt T;Lukas S;Zenger M;Reitberger T;Danzer D;Übner T;Munday DC;Nevels M;Paulus C
通讯作者：
Paulus C
影响因子：
16.6
作者：
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通讯作者：
Jakobsen MR
影响因子：
64.8
作者：
Dou Z;Ghosh K;Vizioli MG;Zhu J;Sen P;Wangensteen KJ;Simithy J;Lan Y;Lin Y;Zhou Z;Capell BC;Xu C;Xu M;Kieckhaefer JE;Jiang T;Shoshkes-Carmel M;Tanim KMAA;Barber GN;Seykora JT;Millar SE;Kaestner KH;Garcia BA;Adams PD;Berger SL
通讯作者：
Berger SL