An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp

• Published in: Nature (London) Vol. 575; no. 7784; pp. 674 - 678
• Main Authors: Ahmad, Shehryar, Wang, Boyuan, Walker, Matthew D., Tran, Hiu-Ki R., Stogios, Peter J., Savchenko, Alexei, Grant, Robert A., McArthur, Andrew G., Laub, Michael T., Whitney, John C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2019; Nature Publishing Group
• Subjects: 631/326/1320; 631/326/41/1319; 631/326/41/1969/2180; 631/326/41/2536; 82/16; 82/58; 82/83; Adenine Nucleotides - biosynthesis; Adenosine; Adenosine - metabolism; Antagonism; Bacteria; Bacteria - drug effects; Bacteria - enzymology; Bacteria - genetics; Bacteria - growth & development; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; bacterial secretion; bacterial structural biology; Bacterial toxins; Bacterial Toxins - chemistry; Bacterial Toxins - genetics; Bacterial Toxins - pharmacology; bacteriology; BASIC BIOLOGICAL SCIENCES; Binding sites; Bioinformatics; Cell death; Cell growth; Cell Wall - drug effects; Cells; Control; Crystal structure; Crystallization; Depletion; Enzymes; Escherichia coli - genetics; Genes; Genomes; Growth; Growth rate; Humanities and Social Sciences; Kinases; Metabolic pathways; Metabolites; multidisciplinary; NMR; Nuclear magnetic resonance; Nucleotides; Opportunist infection; Pathogens; Phosphorylation; Physiological aspects; Proteins; Pseudomonas aeruginosa; Science; Science (multidisciplinary); Secretion; Signal transduction; Structure; Toxins; Toxins, Biological - genetics; Toxins, Biological - toxicity; Type VI Secretion Systems; Canada; United States > US
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1735-9

Bacteria have evolved sophisticated mechanisms to inhibit the growth of competitors
1
. One such mechanism involves type VI secretion systems, which bacteria can use to inject antibacterial toxins directly into neighbouring cells. Many of these toxins target the integrity of the cell envelope, but the full range of growth inhibitory mechanisms remains unknown
2
. Here we identify a type VI secretion effector, Tas1, in the opportunistic pathogen
Pseudomonas aeruginosa
. The crystal structure of Tas1 shows that it is similar to enzymes that synthesize (p)ppGpp, a broadly conserved signalling molecule in bacteria that modulates cell growth rate, particularly in response to nutritional stress
3
. However, Tas1 does not synthesize (p)ppGpp; instead, it pyrophosphorylates adenosine nucleotides to produce (p)ppApp at rates of nearly 180,000 molecules per minute. Consequently, the delivery of Tas1 into competitor cells drives rapid accumulation of (p)ppApp, depletion of ATP, and widespread dysregulation of essential metabolic pathways, thereby resulting in target cell death. Our findings reveal a previously undescribed mechanism for interbacterial antagonism and demonstrate a physiological role for the metabolite (p)ppApp in bacteria.
The bacterium
Pseudomonas aeruginosa
attacks competing bacteria using the toxin Tas1, which pyrophosphorylates adenosine nucleotides to generate (p)ppApp, thereby depleting ATP and disrupting multiple cellular functions.