A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin.
A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin.
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DOI：
10.1016/j.celrep.2018.01.090
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发表时间：
2018-02-20
期刊：
影响因子：
8.8
通讯作者：
Gonzalo S
中科院分区：
文献类型：
--
作者：
Kreienkamp R;Graziano S;Coll-Bonfill N;Bedia-Diaz G;Cybulla E;Vindigni A;Dorsett D;Kubben N;Batista LFZ;Gonzalo S
Hutchinson-Gilford早衰症(HGPS)是一种由截短层粘蛋白A蛋白(孕激素)导致的过早衰老疾病，它会导致细胞和器官的衰退。HGPS患者来源的成纤维细胞积累了基因组的不稳定性，但其潜在的机制和对疾病的贡献仍然知之甚少。在这里，我们表明，孕激素诱导的复制应激(RS)通过引发复制叉(RF)停滞和核酸酶介导的降解来驱动基因组的不稳定性。猖獗的RS伴随着cGAS/STING胞浆DNA传感通路的上调和STAT1调节的干扰素(干扰素)样反应的激活。减少RS和类干扰素反应，尤其是使用骨化三醇，可以改善早衰细胞的健康状况，提高细胞重新编程的效率。重要的是，其他改善HGPS表型的化合物可以减少RS和干扰素样反应。我们的研究揭示了孕激素毒性的潜在机制，包括RS诱导的基因组不稳定和干扰素样反应的激活，以及它们与HGP中细胞衰退的相关性。Kreienkamp等人。揭示早衰疾病Hutchinson-Gilford早衰症的细胞衰退机制。孕激素是导致这种疾病的突变蛋白，它会引发复制压力和细胞固有的先天免疫反应。这项研究确定了一些策略，如骨化三醇，可以挽救这些表型并使早衰细胞恢复活力。
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by a truncated lamin A protein (progerin) that drives cellular and organismal decline. HGPS patient-derived fibroblasts accumulate genomic instability, but its underlying mechanisms and contribution to disease remain poorly understood. Here, we show that progerin-induced replication stress (RS) drives genomic instability by eliciting replication fork (RF) stalling and nuclease-mediated degradation. Rampant RS is accompanied by upregulation of the cGAS/STING cytosolic DNA sensing pathway and activation of a robust STAT1-regulated interferon (IFN)-like response. Reducing RS and the IFN-like response, especially with calcitriol, improves the fitness of progeria cells and increases the efficiency of cellular reprogramming. Importantly, other compounds that improve HGPS phenotypes reduce RS and the IFN-like response. Our study reveals mechanisms underlying progerin toxicity, including RS-induced genomic instability and activation of IFN-like responses, and their relevance for cellular decline in HGPS. Kreienkamp et al. reveal mechanisms underlying cellular decline in the premature aging disease Hutchinson-Gilford progeria syndrome. Progerin, the mutant protein that causes this disease, elicits replication stress and a cell-intrinsic innate immune response. The study identifies strategies, such as calcitriol, that rescue these phenotypes and rejuvenate progeria cells.
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影响因子：
7.5
作者：
Gonzalo S;Kreienkamp R
通讯作者：
Kreienkamp R
影响因子：
7.7
作者：
Chojnowski A;Ong PF;Wong ES;Lim JS;Mutalif RA;Navasankari R;Dutta B;Yang H;Liow YY;Sze SK;Boudier T;Wright GD;Colman A;Burke B;Stewart CL;Dreesen O
通讯作者：
Dreesen O
影响因子：
17.1
作者：
Cao, Kan;Graziotto, John J.;Collins, Francis S.
通讯作者：
Collins, Francis S.
影响因子：
64.5
作者：
Gordon LB;Rothman FG;López-Otín C;Misteli T
通讯作者：
Misteli T
DOI：
10.1016/j.ymeth.2015.08.024
发表时间：
2016-03-01
期刊：
Methods (San Diego, Calif.)
影响因子：
--
作者：
Kubben N;Brimacombe KR;Donegan M;Li Z;Misteli T
通讯作者：
Misteli T