An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp
Abstract
Bacteria have evolved sophisticated mechanisms to inhibit the growth of competitors. 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. In this study 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. 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.
- Authors:
-
- McMaster Univ., Hamilton, ON (Canada)
- Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
- Univ. of Toronto, ON (Canada); Center for Structural Genomics of Infectious Diseases (CSGID), Toronto (Canada)
- Univ. of Toronto, ON (Canada); Center for Structural Genomics of Infectious Diseases (CSGID), Toronto (Canada); Univ. of Calgary, AB (Canada)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH); USHHS; Canadian Foundation for Innovation; Canadian Institutes of Health Research (CIHR)
- OSTI Identifier:
- 1578213
- Grant/Contract Number:
- AC02-06CH11357; HHSN272201200026C; HHSN272201700060C; P30GM124165; S10OD021527; 34531; R01-GM082899; PJT-156129
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature (London)
- Additional Journal Information:
- Journal Name: Nature (London); Journal Volume: 575; Journal Issue: 7784; Journal ID: ISSN 0028-0836
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; bacterial secretion; bacterial structural biology; bacterial toxins; bacteriology
Citation Formats
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., and Whitney, John C. An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp. United States: N. p., 2019.
Web. doi:10.1038/s41586-019-1735-9.
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. An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp. United States. https://doi.org/10.1038/s41586-019-1735-9
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., and Whitney, John C. Wed .
"An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp". United States. https://doi.org/10.1038/s41586-019-1735-9. https://www.osti.gov/servlets/purl/1578213.
@article{osti_1578213,
title = {An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp},
author = {Ahmad, Shehryar and Wang, Boyuan and Walker, Matthew D. and Tran, Hiu-Ki R. and Stogios, Peter J. and Savchenko, Alexei and Grant, Robert A. and McArthur, Andrew G. and Laub, Michael T. and Whitney, John C.},
abstractNote = {Bacteria have evolved sophisticated mechanisms to inhibit the growth of competitors. 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. In this study 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. 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.},
doi = {10.1038/s41586-019-1735-9},
journal = {Nature (London)},
number = 7784,
volume = 575,
place = {United States},
year = {Wed Nov 06 00:00:00 EST 2019},
month = {Wed Nov 06 00:00:00 EST 2019}
}
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