2’3’-cGAMP binds and activates Rab18 to promote cell migration

Cyclic dinucleotides serve as bacterial secondary messengers regulating sporulation, motility, biofilm formation and virulence. A nonsymmetric c-di-GAMP is firstly identified in bacteria to promote colonization, while mammalian 2’3’-cGAMP is synthesized by cGAS through binding and activating STING to trigger innate immune activation. However, pathophysiological function of 2’3’-cGAMP beyond innate immunity remains elusive. Here, we report 2’3’-cGAMP facilitates cell migration independent of STING and its innate immune function. 2’3’-cGAMP interactome analysis with a targeted shRNA-screen identifies the GTPase Rab18 as a direct 2’3’-cGAMP binding partner and effector in cell migration control. Mechanistically, 2’3’-cGAMP binds Rab18-S17, E36 and R92 residues to facilitate Rab18 activation and subsequently promotes FosB transcription in promoting cell migration. Low-dose doxorubicin induces 2’3’-cGAMP synthesis and facilitates cell migration in vitro and in vivo. Interestingly, lovastatin induces Rab18 phosphorylation abolishes 2’3’-cGAMP recognition to antagonize 2’3’-cGAMP induced cell migration. Together, our study reveals a novel 2’3’-cGAMP function in cell migration control beyond innate immunity via binding Rab18 that provides new insights into clinical applications of 2’3’-cGAMP.