State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China.
Nanhu Laboratory, Jiaxing, China.
EMBO Rep. 2022 Jan 5;23(1):e53166. doi: 10.15252/embr.202153166. Epub 2021 Nov 15.
Cyclic GMP-AMP synthase (cGAS) functions as a key sensor for microbial invasion and cellular damage by detecting emerging cytosolic DNA. Here, we report that GTPase-activating protein-(SH3 domain)-binding protein 1 (G3BP1) primes cGAS for its prompt activation by engaging cGAS in a primary liquid-phase condensation state. Using high-resolution microscopy, we show that in resting cells, cGAS exhibits particle-like morphological characteristics, which are markedly weakened when G3BP1 is deleted. Upon DNA challenge, the pre-condensed cGAS undergoes liquid-liquid phase separation (LLPS) more efficiently. Importantly, G3BP1 deficiency or its inhibition dramatically diminishes DNA-induced LLPS and the subsequent activation of cGAS. Interestingly, RNA, previously reported to form condensates with cGAS, does not activate cGAS. Accordingly, we find that DNA - but not RNA - treatment leads to the dissociation of G3BP1 from cGAS. Taken together, our study shows that the primary condensation state of cGAS is critical for its rapid response to DNA.
环鸟苷酸-腺苷酸合酶（cGAS）通过检测细胞质 DNA 的出现，作为微生物入侵和细胞损伤的关键传感器发挥作用。在这里，我们报告 GTPase 激活蛋白-(SH3 结构域)-结合蛋白 1（G3BP1）通过将 cGAS 募集到初始液相凝聚状态，为其快速激活做好准备。通过高分辨率显微镜，我们发现在静止细胞中，cGAS 表现出颗粒状形态特征，当 G3BP1 缺失时，这些特征明显减弱。在 DNA 刺激下，预凝聚的 cGAS 更有效地进行液-液相分离（LLPS）。重要的是，G3BP1 缺失或抑制显著降低了 DNA 诱导的 LLPS 以及随后 cGAS 的激活。有趣的是，先前报道与 cGAS 形成凝聚物的 RNA 并不能激活 cGAS。因此，我们发现 DNA - 而不是 RNA - 处理会导致 G3BP1 从 cGAS 上解离。综上所述，我们的研究表明，cGAS 的初始凝聚状态对于其对 DNA 的快速反应至关重要。
