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 <i>S. aureus</i> 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.
Authors
- Jeremy M. Simon (ORCID: https://orcid.org/0000-0003-3906-1663)
- Qi Zhang (ORCID: https://orcid.org/0000-0003-1754-4058)
- Brenda Temple (ORCID: https://orcid.org/0000-0002-9233-0191)
- Sharon L. Campbell (ORCID: https://orcid.org/0000-0003-0311-409X)
- Blossom Damania (ORCID: https://orcid.org/0000-0002-9205-1774)
- Jian Wang (ORCID: https://orcid.org/0000-0001-7768-2802)
- Joshua A. Boyer (ORCID: https://orcid.org/0000-0002-3990-4096)
- Nikolay V. Dokholyan
- Albert S. Baldwin (ORCID: https://orcid.org/0000-0003-1246-1333)
- Austin J. Hepperla (ORCID: https://orcid.org/0000-0002-0107-2001)
- Laura E. Herring (ORCID: https://orcid.org/0000-0003-4496-7312)
- Pengda Liu (ORCID: https://orcid.org/0000-0003-2755-3601)
- Leiah M. Carey (ORCID: https://orcid.org/0000-0002-6103-2933)
- Quentin Hahn (ORCID: https://orcid.org/0000-0003-3510-8364)
- Zhigang Zhang (ORCID: https://orcid.org/0000-0002-4974-5850)
- Xiaodong Wang (ORCID: https://orcid.org/0000-0003-3293-7538)
- Yanqiong Zhang (ORCID: https://orcid.org/0000-0002-2428-8956)
- Yu Deng (ORCID: https://orcid.org/0000-0002-3264-0809)
- Zhichuan Zhu (ORCID: https://orcid.org/0000-0003-0327-9978)
- Jonathan E. Frank
- Deyu Kong (ORCID: https://orcid.org/0000-0002-9154-5967)
- Charlene Santos (ORCID: https://orcid.org/0000-0002-6439-6097)
- Le Yu (ORCID: https://orcid.org/0000-0002-5898-8088)
Institutions
- University of North Carolina at Chapel Hill (US)
- Pennsylvania State University (US)
- University of North Carolina Health Care (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1126/sciadv.ado7024
- Citations
- 4
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.96