Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments in senescent cells. The activation of cGAS, in turn, triggers the production of SASP factors via stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS–STING pathway in vitro and we show cGAS-dependent regulation of senescence following irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS–STING pathway as a crucial regulator of senescence and the SASP.

中文翻译：

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通过cGAS对细胞质染色质片段的先天免疫感应促进衰老

细胞衰老是由各种不同的压力触发的，并以永久性的细胞周期停滞为特征。衰老细胞分泌多种炎症因子，统称为衰老相关分泌表型（SASP）。对SASP调节的基本机制仍不完全了解。在这里，我们定义了先天DNA感应在衰老和SASP调控中的作用。我们发现，环状GMP-AMP合酶（cGAS）识别衰老细胞中的胞质染色质片段。cGAS的激活反过来通过干扰素基因（STING）的刺激物触发SASP因子的产生，从而促进旁分泌衰老。我们证明了细胞衰老的多种刺激在体外参与了cGAS–STING途径并且我们显示了cGAS依赖的辐射照射和体内癌基因激活后的衰老调节。我们的发现通过建立cGAS-STING途径作为衰老和SASP的重要调节剂，为了解细胞衰老的机制提供了见识。