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

Shehryar Ahmad, Boyuan Wang, Matthew D. Walker, Hiu-Ki R. Tran, Peter J. Stogios, Alexei Savchenko, Robert A. Grant, Andrew G. McArthur, Michael T. Laub () and John C. Whitney ()
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Shehryar Ahmad: McMaster University
Boyuan Wang: Massachusetts Institute of Technology
Matthew D. Walker: McMaster University
Hiu-Ki R. Tran: McMaster University
Peter J. Stogios: University of Toronto
Alexei Savchenko: University of Toronto
Robert A. Grant: Massachusetts Institute of Technology
Andrew G. McArthur: McMaster University
Michael T. Laub: Massachusetts Institute of Technology
John C. Whitney: McMaster University

Nature, 2019, vol. 575, issue 7784, 674-678

Abstract: Abstract Bacteria have evolved sophisticated mechanisms to inhibit the growth of competitors1. 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 unknown2. 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 stress3. 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.

Date: 2019
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DOI: 10.1038/s41586-019-1735-9

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