Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, PA, 19104, USA.
Nat Commun. 2020 Feb 19;11(1):908. doi: 10.1038/s41467-020-14652-y.
Cyclic cGMP-AMP synthase (cGAS) is a pattern recognition cytosolic DNA sensor that is essential for cellular senescence. cGAS promotes inflammatory senescence-associated secretory phenotype (SASP) through recognizing cytoplasmic chromatin during senescence. cGAS-mediated inflammation is essential for the antitumor effects of immune checkpoint blockade. However, the mechanism by which cGAS recognizes cytoplasmic chromatin is unknown. Here we show that topoisomerase 1-DNA covalent cleavage complex (TOP1cc) is both necessary and sufficient for cGAS-mediated cytoplasmic chromatin recognition and SASP during senescence. TOP1cc localizes to cytoplasmic chromatin and TOP1 interacts with cGAS to enhance the binding of cGAS to DNA. Retention of TOP1cc to cytoplasmic chromatin depends on its stabilization by the chromatin architecture protein HMGB2. Functionally, the HMGB2-TOP1cc-cGAS axis determines the response of orthotopically transplanted ex vivo therapy-induced senescent cells to immune checkpoint blockade in vivo. Together, these findings establish a HMGB2-TOP1cc-cGAS axis that enables cytoplasmic chromatin recognition and response to immune checkpoint blockade.
环鸟苷酸-腺苷酸合酶（cGAS）是一种模式识别细胞质 DNA 传感器，对细胞衰老至关重要。cGAS 在衰老过程中通过识别细胞质染色质来促进炎症性衰老相关分泌表型（SASP）。cGAS 介导的炎症对于免疫检查点阻断的抗肿瘤作用至关重要。然而，cGAS 识别细胞质染色质的机制尚不清楚。在这里，我们表明拓扑异构酶 1-DNA 共价断裂复合物（TOP1cc）对于 cGAS 介导的细胞质染色质识别和衰老过程中的 SASP 是必要和充分的。TOP1cc 定位于细胞质染色质，TOP1 与 cGAS 相互作用以增强 cGAS 与 DNA 的结合。TOP1cc 保留在细胞质染色质上取决于其由染色质结构蛋白 HMGB2 稳定。功能上，HMGB2-TOP1cc-cGAS 轴决定了原位移植的体外治疗诱导衰老细胞对体内免疫检查点阻断的反应。总之，这些发现确立了一个 HMGB2-TOP1cc-cGAS 轴，该轴能够识别细胞质染色质并对免疫检查点阻断作出反应。
