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

Sci Adv. 2024 Oct 18;10(42):eado7024. doi: 10.1126/sciadv.ado7024. Epub 2024 Oct 16.

Abstract

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.

MeSH terms

  • Animals
  • Cell Movement* / drug effects
  • Humans
  • Immunity, Innate*
  • Lovastatin / pharmacology
  • Mice
  • Protein Binding
  • Proto-Oncogene Proteins c-fos / metabolism
  • Signal Transduction*
  • Staphylococcus aureus
  • rab GTP-Binding Proteins* / metabolism

Substances

  • Lovastatin
  • Proto-Oncogene Proteins c-fos
  • rab GTP-Binding Proteins
  • RAB18 protein, human
  • Rab18 protein, mouse
  • FOSB protein, human
  • Fosb protein, mouse