STING enhances cell death through regulation of reactive oxygen species and DNA damage.
STING enhances cell death through regulation of reactive oxygen species and DNA damage.
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STING通过调节活性氧物种和DNA损伤来促进细胞死亡。
DOI：
10.1038/s41467-021-22572-8
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发表时间：
2021-04-19
影响因子：
16.6
通讯作者：
Contessa JN
中科院分区：
文献类型：
--
作者：
Hayman TJ;Baro M;MacNeil T;Phoomak C;Aung TN;Cui W;Leach K;Iyer R;Challa S;Sandoval-Schaefer T;Burtness BA;Rimm DL;Contessa JN
对DNA损伤剂的耐药性是肿瘤治疗失败和不良结局的重要原因。为了识别未被识别的细胞存活调节因子，我们使用电离辐射作为选择压力进行了全基因组CRISPR-Cas9筛选，并将STING（干扰素基因刺激因子）鉴定为肿瘤细胞存活的内在调节因子。我们表明，STING调节一个转录程序，控制活性氧（ROS）的产生，STING的损失改变ROS的稳态，以减少DNA损伤，并导致治疗耐药性。与这些数据一致，来自头颈部鳞状细胞癌患者标本的肿瘤分析显示，低STING表达与更差的结果相关。我们还证明，STING的药理学激活增强了体内电离辐射的作用，为STING激动剂和DNA损伤剂的治疗组合提供了理论基础。这些结果突出了STING的作用，其超出了其在环状二核苷酸和DNA损伤传感中的典型功能，并将STING鉴定为细胞ROS稳态和肿瘤细胞对活性氧依赖性DNA损伤剂的易感性的调节剂。内质网定位的衔接子STING通过其感知DNA损伤的能力来调节先天性免疫应答。在这里，作者揭示了STING作为细胞ROS稳态和肿瘤细胞对活性氧依赖性DNA损伤剂的易感性的调节剂发挥作用。
Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. To identify unrecognized regulators of cell survival we performed a whole-genome CRISPR-Cas9 screen using treatment with ionizing radiation as a selective pressure, and identified STING (stimulator of interferon genes) as an intrinsic regulator of tumor cell survival. We show that STING regulates a transcriptional program that controls the generation of reactive oxygen species (ROS), and that STING loss alters ROS homeostasis to reduce DNA damage and to cause therapeutic resistance. In agreement with these data, analysis of tumors from head and neck squamous cell carcinoma patient specimens show that low STING expression is associated with worse outcomes. We also demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents. These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents. The endoplasmic reticulum-localized adaptor STING regulates the innate immune response through its ability to sense DNA damage. Here the authors reveal that STING functions as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.
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影响因子：
11.2
作者：
Burnette BC;Liang H;Lee Y;Chlewicki L;Khodarev NN;Weichselbaum RR;Fu YX;Auh SL
通讯作者：
Auh SL
DOI：
10.1126/science.1203430
发表时间：
2011-06-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cotta-Ramusino C;McDonald ER 3rd;Hurov K;Sowa ME;Harper JW;Elledge SJ
通讯作者：
Elledge SJ
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。
影响因子：
16
作者：
Dunphy G;Flannery SM;Almine JF;Connolly DJ;Paulus C;Jønsson KL;Jakobsen MR;Nevels MM;Bowie AG;Unterholzner L
通讯作者：
Unterholzner L
影响因子：
--
作者：
Huo Y;Zong Z;Wang Q;Zhang Z;Deng H
通讯作者：
Deng H
影响因子：
22.7
作者：
Carozza JA;Böhnert V;Nguyen KC;Skariah G;Shaw KE;Brown JA;Rafat M;von Eyben R;Graves EE;Glenn JS;Smith M;Li L
通讯作者：
Li L