The Rab18/Ras/ERK/FosB/MMP3 Signaling Pathway Mediates Cell Migration Regulation by 2′3′-cGAMP

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.