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Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E6048-E6055. doi: 10.1073/pnas.1801233115. Epub 2018 Jun 11.

Direct activation of a phospholipase by cyclic GMP-AMP in El Tor Vibrio cholerae.

Author information

1
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824.
2
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111.
3
Graduate Program in Molecular Microbiology, Tufts Sackler School of Biomedical Sciences, Boston, MA 02111.
4
Michigan State University-Department of Energy Plant Research Laboratory, Michigan State University, East Lansing, MI 48824.
5
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824.
6
Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103.
7
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824; watersc3@msu.edu Wai-Leung.Ng@tufts.edu.
8
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111; watersc3@msu.edu Wai-Leung.Ng@tufts.edu.

Abstract

Sensing and responding to environmental changes is essential for bacteria to adapt and thrive, and nucleotide-derived second messengers are central signaling systems in this process. The most recently identified bacterial cyclic dinucleotide second messenger, 3', 3'-cyclic GMP-AMP (cGAMP), was first discovered in the El Tor biotype of Vibrio cholerae The cGAMP synthase, DncV, is encoded on the VSP-1 pathogenicity island, which is found in all El Tor isolates that are responsible for the current seventh pandemic of cholera but not in the classical biotype. We determined that unregulated production of DncV inhibits growth in El Tor V. cholerae but has no effect on the classical biotype. This cGAMP-dependent phenotype can be suppressed by null mutations in vc0178 immediately 5' of dncV in VSP-1. VC0178 [renamed as cGAMP-activated phospholipase in Vibrio (CapV)] is predicted to be a patatin-like phospholipase, and coexpression of capV and dncV is sufficient to induce growth inhibition in classical V. cholerae and Escherichia coli Furthermore, cGAMP binds to CapV and directly activates its hydrolase activity in vitro. CapV activated by cGAMP in vivo degrades phospholipids in the cell membrane, releasing 16:1 and 18:1 free fatty acids. Together, we demonstrate that cGAMP activates CapV phospholipase activity to target the cell membrane and suggest that acquisition of this second messenger signaling pathway may contribute to the emergence of the El Tor biotype as the etiological agent behind the seventh cholera pandemic.

KEYWORDS:

cGAMP; cyclic dinucleotides; pathogenicity island; phospholipid metabolism; second messengers

PMID:
29891656
PMCID:
PMC6042076
DOI:
10.1073/pnas.1801233115
[Indexed for MEDLINE]
Free PMC Article

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