Deng Yu, Yuan Runjie, Liu Pengda
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Int J Mol Sci. 2025 Jun 16;26(12):5758. doi: 10.3390/ijms26125758.
The unique secondary messenger 2'3'-cGAMP, produced by cGAS in response to cytosolic dsDNA, plays a critical role in activating innate immunity by binding to and activating STING via cell-intrinsic, autocrine, or paracrine mechanisms. Recently, we identified Rab18 as a novel, STING-independent binder of 2'3'-cGAMP. Binding of 2'3'-cGAMP to Rab18 promotes Rab18 activation and induces cell migration. However, the downstream mechanisms by which 2'3'-cGAMP-induced Rab18 activation regulates cell migration remain largely unclear. Herein, using phospho-profiling analysis, we identify MAPK signaling as a key downstream effector of the 2'3'-cGAMP/Rab18 axis that promotes the expression of FosB2 and drives cell migration. Furthermore, we identify MMP3 as a major transcriptional target of FosB2, through which the 2'3'-cGAMP/Rab18/MAPK/FosB2 signaling pathway positively regulates cell migration. Together, our findings provide new mechanistic insights into how 2'3'-cGAMP signaling controls cell migration and suggest the potential of MAPK inhibitors to block 2'3'-cGAMP-induced migratory responses.
由cGAS响应胞质双链DNA产生的独特第二信使2'3'-cGAMP，通过细胞内、自分泌或旁分泌机制与STING结合并激活STING，在激活先天免疫中发挥关键作用。最近，我们鉴定出Rab18是2'3'-cGAMP一种新的、不依赖STING的结合蛋白。2'3'-cGAMP与Rab18的结合促进Rab18激活并诱导细胞迁移。然而，2'3'-cGAMP诱导的Rab18激活调节细胞迁移的下游机制仍 largely不清楚。在此，我们使用磷酸化分析，确定MAPK信号传导是2'3'-cGAMP/Rab18轴的关键下游效应器，它促进FosB2的表达并驱动细胞迁移。此外，我们确定MMP3是FosB2的主要转录靶点，通过它2'3'-cGAMP/Rab18/MAPK/FosB2信号通路正向调节细胞迁移。总之，我们的研究结果为2'3'-cGAMP信号如何控制细胞迁移提供了新的机制见解，并提示MAPK抑制剂可能阻断2'3'-cGAMP诱导的迁移反应。
