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

Yu Deng; Quentin Hahn; Le Yu; Zhichuan Zhu; Joshua A Boyer; Jian Wang; Deyu Kong; Leiah M Carey; Austin J Hepperla; Jeremy M Simon; Brenda Temple; Zhigang Zhang; Yanqiong Zhang; Charlene Santos; Jonathan E Frank; Laura E Herring; Xiaodong Wang; Nikolay V Dokholyan; Sharon L Campbell; Albert S Baldwin; Blossom Damania; Qi Zhang; Pengda Liu

doi:10.1126/sciadv.ado7024

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.

Authors

Yu Deng^{1

2}, Quentin Hahn², Le Yu^{1

2}, Zhichuan Zhu^{1

2}, Joshua A Boyer², Jian Wang^{3

4

5}, Deyu Kong⁶, Leiah M Carey^{1

2}, Austin J Hepperla^{1

7

8}, Jeremy M Simon^{1

7

8

9

10}, Brenda Temple², Zhigang Zhang^{1

11

12}, Yanqiong Zhang^{1

2}, Charlene Santos¹³, Jonathan E Frank¹⁴, Laura E Herring¹⁵, Xiaodong Wang^{1

6}, Nikolay V Dokholyan^{3

4

5}, Sharon L Campbell^{1

2}, Albert S Baldwin¹, Blossom Damania^{1

11

12}, Qi Zhang², Pengda Liu^{1

2}

Affiliations

¹ Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA.
⁴ Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 17033, USA.
⁵ Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, USA.
⁶ Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁸ UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁰ Department of Data Science, Dana-Farber Cancer Institute Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
¹¹ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹² University of North Carolina Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹³ UNC Animal Studies Core Facility, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁴ UNC Small Animal Imaging Core Facility, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁵ UNC Proteomics Core Facility, Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

PMID: 39413198
DOI: 10.1126/sciadv.ado7024

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

rab GTP-Binding Proteins
Proto-Oncogene Proteins c-fos
Lovastatin