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

Abstract

SignificanceSecond messengers are employed by all organisms to regulate fundamental behaviors, including biofilm formation, motility, metabolism, and pathogenesis in bacteria. We have identified a phospholipase in the El Tor Vibrio cholerae biotype, responsible for the current cholera pandemic, that is directly activated by the second messenger 3′, 3′-cyclic GMP-AMP (cGAMP). Discovery of this proteinaceous bacterial cGAMP effector sheds light on the functions and basic principles of cGAMP signaling. Both this phospholipase and the cGAMP synthase are encoded within the VSP-1 pathogenicity island, unique to the El Tor biotype, and our findings assign a biochemical function to VSP-1 that may contribute to the epidemiological success of El Tor V. cholerae.

The interactions between cGAS-STING pathway and pathogens

“…The activation of phospholipase results in bacterial membrane degradation and cell death, thereby preventing further infection and propagation of the phage. 44,45 Notably, in some bacteria and primitive eukaryotes, the effector gene in the potential anti-phage operon contains a Toll-interleukin (IL) receptor (TIR) domain, instead of a phospholipase domain, and a STING domain, although how this operon executes its function is unclear. 45 Overall, these results suggest that the origin and antimicrobial functions of cGAS and STING span far beyond the mammals and may even predate the phylogeny of animals.…”

Pathogenicity and virulence regulation of Vibrio cholerae at the interface of host-gut microbiome interactions

“…Additionally, the most recently identified bacterial cyclic dinucleotide signaling molecule, the hybrid 3′, 3′-cyclic GMP-AMP (cGAMP), is synthesized by the enzyme DncV, whose expression is regulated by the master virulence regulator ToxT [102]. cGAMP binds to the effector called CapV, a phospholipase, and regulates virulence, chemotaxis, and fatty acid metabolic genes [103].…”

Regulatory Hierarchies Controlling Virulence Gene Expression in Shigella flexneri and Vibrio cholerae

“…When made stable by the Hfq RNA chaperone, TarB down-regulates the VspR transcription repressor resulting in derepression of virulence genes in the Vibrio seventh pandemic pathogenicity island VSP-1 in 7PET V. cholerae ( Davies et al, 2012 ). The expression of these genes produces increased intracellular concentrations of signaling molecules such as cyclic-GMP/cyclic-AMP and possibly c-di-GMP/c-di-AMP, altering the metabolism of the bacterium and its chemotactic behavior ( Davies et al, 2012 ; Dorman, 2015 ; Severin et al, 2018 ) (Figure 3 ). TarB also post-transcriptionally down-regulates TcpF production from VPI-1: here, Hfq does not seem to be required and the production of the sRNA is enhanced during anaerobic growth ( Bradley et al, 2011 ) (Figure 3 ).…”