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

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 description

Bibliographic Details
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.
Other Authors: Massachusetts Institute of Technology. Department of Biology
Format: Article
Language:English
Published: Springer Science and Business Media LLC 2020
Online Access:https://hdl.handle.net/1721.1/125211
_version_ 1826201677388054528
author 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.
author2 Massachusetts Institute of Technology. Department of Biology
author_facet Massachusetts Institute of Technology. Department of Biology
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.
author_sort Ahmad, Shehryar
collection MIT
description 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.
first_indexed 2024-09-23T11:55:05Z
format Article
id mit-1721.1/125211
institution Massachusetts Institute of Technology
language English
last_indexed 2024-09-23T11:55:05Z
publishDate 2020
publisher Springer Science and Business Media LLC
record_format dspace
spelling mit-1721.1/1252112022-10-01T06:58:40Z An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp 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. Massachusetts Institute of Technology. Department of Biology 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. National Institutes of Health (Grant R01-GM082899) 2020-05-13T15:51:00Z 2020-05-13T15:51:00Z 2019-11 2019-05 2020-05-11T15:56:29Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 https://hdl.handle.net/1721.1/125211 Ahmad, Shehryar et al. "An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp." Nature 575, 7784 (November 2019): 674–678 © 2019 The Author(s) en http://dx.doi.org/10.1038/s41586-019-1735-9 Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Science and Business Media LLC PMC
spellingShingle 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
title An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp
title_full An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp
title_fullStr An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp
title_full_unstemmed An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp
title_short An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp
title_sort interbacterial toxin inhibits target cell growth by synthesizing p ppapp
url https://hdl.handle.net/1721.1/125211
work_keys_str_mv AT ahmadshehryar aninterbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT wangboyuan aninterbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT walkermatthewd aninterbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT tranhiukir aninterbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT stogiospeterj aninterbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT savchenkoalexei aninterbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT grantroberta aninterbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT mcarthurandrewg aninterbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT laubmichaelt aninterbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT whitneyjohnc aninterbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT ahmadshehryar interbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT wangboyuan interbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT walkermatthewd interbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT tranhiukir interbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT stogiospeterj interbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT savchenkoalexei interbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT grantroberta interbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT mcarthurandrewg interbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT laubmichaelt interbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp
AT whitneyjohnc interbacterialtoxininhibitstargetcellgrowthbysynthesizingpppapp