An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp
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abstract
Bacteria have evolved sophisticated mechanisms to inhibit the growth of competitors. One such mechanism involves type VI secretion systems, which can be used by bacteria to directly inject antibacterial toxins into neighbouring cells. Many of these toxins target cell envelope integrity, but the full range of growth inhibitory mechanisms remains to be determined. Here, we discover a novel type VI secretion effector, Tas1, in the opportunistic pathogen Pseudomonas aeruginosa. A crystal structure of Tas1 reveals similarity to enzymes that synthesize (p)ppGpp, a broadly conserved signaling molecule in bacteria that modulates cell growth rate, particularly in response to nutritional stress. Strikingly, however, we find that Tas1 does not synthesize (p)ppGpp, and instead pyrophosphorylates adenosine nucleotides to produce (p)ppApp at rates of nearly 180,000 per minute. Consequently, delivery of Tas1 into competitor cells drives the rapid accumulation of (p)ppApp, depletion of ATP, and widespread dysregulation of essential metabolic pathways, resulting in target cell death. Collectively, our findings reveal a new mechanism for interbacterial antagonism and demonstrate, for the first time, a physiological role for the metabolite (p)ppApp in bacteria.Support or Funding InformationCanadian Institutes of Health Research, David Braley Centre for Antibiotic Discovery, National Institutes of Health, Howard Hughes Medical InstituteStructure of the (p)ppApp synthetase toxin Tas1 in complex with its cognate immunity protein, Tis1.Figure 1Tas1 is a pyrophosphokinase that is specific for canonical 5′‐adenosine nucleotides.Figure 2
