cGAS surveillance of micronuclei links genome instability to innate immunity.
cGAS surveillance of micronuclei links genome instability to innate immunity.
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DOI：
10.1038/nature23449
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发表时间：
2017-08-24
期刊：
影响因子：
64.8
通讯作者：
Jackson AP
中科院分区：
文献类型：
--
作者：
Mackenzie KJ;Carroll P;Martin CA;Murina O;Fluteau A;Simpson DJ;Olova N;Sutcliffe H;Rainger JK;Leitch A;Osborn RT;Wheeler AP;Nowotny M;Gilbert N;Chandra T;Reijns MAM;Jackson AP
DNA 在细胞核内被严格划分以防止自身免疫；尽管如此，cGAS（一种 dsDNA 的胞质传感器）在自身炎症性疾病和 DNA 损伤中被激活。细胞 DNA 究竟如何进入细胞质仍有待确定。在这里，我们报告说，cGAS 定位于单基因自身炎症模型中基因组不稳定性产生的微核，在外源 DNA 损伤后并在人类癌细胞中自发出现。这些微核在细胞分裂过程中 DNA 错误分离后出现，由被自身核膜包围的染色质组成。微核包膜的破坏是与染色质碎裂相关的过程，导致 cGAS 快速积累，从而提供了一种使自身 DNA 暴露于细胞质的机制。 cGAS 与染色质结合并被染色质激活，并且与有丝分裂起源一致，微核形成和 DNA 损伤后的促炎反应是细胞周期依赖性的。此外，通过将活细胞激光显微切割与单细胞转录组学相结合，我们确定干扰素刺激的基因表达的诱导发生在微核细胞中。因此，我们得出结论，微核代表了免疫刺激 DNA 的重要来源。由于滞后染色体形成的微核也会激活该途径，因此微核的 cGAS 识别可能充当细胞固有的免疫监视机制，检测一系列肿瘤诱发过程。
DNA is strictly compartmentalised within the nucleus to prevent autoimmunity; despite this cGAS, a cytosolic sensor of dsDNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localises to micronuclei arising from genome instability in a model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. These micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by their own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS binds to and is activated by chromatin and, consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA-damage are cell-cycle dependent. Furthermore, by combining live-cell laser microdissection with single cell transcriptomics, we establish that induction of interferon stimulated gene expression occurs in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, cGAS recognition of micronuclei may act as a cell-intrinsic immune surveillance mechanism detecting a range of neoplasia-inducing processes.
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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：
5.6
作者：
Huynh, VAT;Robinson, PJJ;Rhodes, D
通讯作者：
Rhodes, D
DOI：
10.1083/jcb.200607133
发表时间：
2007-05-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gilbert N;Thomson I;Boyle S;Allan J;Ramsahoye B;Bickmore WA
通讯作者：
Bickmore WA
影响因子：
6
作者：
Gisselsson, D;Björk, J;Mandahl, N
通讯作者：
Mandahl, N
影响因子：
48
作者：
Kharchenko, Peter V.;Silberstein, Lev;Scadden, David T.
通讯作者：
Scadden, David T.