Cytoplasmic chromatin triggers inflammation in senescence and cancer.
Cytoplasmic chromatin triggers inflammation in senescence and cancer.
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DOI：
10.1038/nature24050
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发表时间：
2017-10-19
期刊：
影响因子：
64.8
通讯作者：
Berger SL
中科院分区：
文献类型：
--
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
染色质传统上被认为是调控基因表达和沉默的核实体。然而，我们最近发现了细胞质染色质片段的存在，这些片段在衰老期间从原代细胞的完整细胞核中脱落，这是一种与促炎反应相关的终末细胞周期阻滞形式。染色质在细胞质中的功能意义尚不清楚。在这里，我们发现细胞质染色质激活先天免疫细胞质DNA感应cGAS-STING通路，导致短期炎症以抑制激活的癌基因和与组织破坏和癌症相关的慢性炎症。细胞质染色质- cgas - sting通路促进人类细胞和小鼠的衰老相关分泌表型（SASP）。缺乏STING的小鼠表现出对致癌RAS的免疫监视受损，并在电离辐射下减少组织炎症。此外，这一途径在癌细胞中被激活，并与人类癌症中的促炎基因表达相关。总的来说，我们的研究结果表明，基因组DNA在衰老和癌症的细胞质中起着启动促炎途径的作用。靶向细胞质染色质介导的途径可能在治疗炎症相关疾病方面有希望。
Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA sensing cGAS-STING pathway, leading to both short-term inflammation to restrain activated oncogene and chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype (SASP) in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.
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影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
影响因子：
3.3
作者：
Freund A;Laberge RM;Demaria M;Campisi J
通讯作者：
Campisi J
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
10.5
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
通讯作者：
Lowe, Scott W.