2′3′-cGAMP interactome identifies 2′3′-cGAMP/Rab18/FosB signaling in cell migration control independent of innate immunity

c-di-GAMP was first identified in bacteria to promote colonization, while mammalian 2′3′-cGAMP is synthesized by cGAS to activate STING for innate immune stimulation. However, 2′3′-cGAMP function beyond innate immunity remains elusive. Here, we report that 2′3′-cGAMP promotes cell migration independent of innate immunity. 2′3′-cGAMP interactome analysis identifies the small GTPase Rab18 as a 2′3′-cGAMP binding partner and effector in cell migration control. Mechanistically, 2′3′-cGAMP binds Rab18 to facilitate GTP loading and subsequent Rab18 activation, which further promotes FosB transcription in facilitating cell migration. Induced synthesis of endogenous 2′3′-cGAMP by intrabreast tumor bacterium S. aureus infection or low-dose doxorubicin treatment facilitates cell migration depending on the cGAS/cGAMP/Rab18/FosB signaling. We find that lovastatin induces Rab18 deprenylation that abolishes 2′3′-cGAMP recognition therefore suppressing cell migration. Together, our study reveals a previously unidentified 2′3′-cGAMP function in cell migration control via the 2′3′-cGAMP/Rab18/FosB signaling that provides additional insights into clinical applications of 2′3′-cGAMP.