Editors' ChoiceHost-Pathogen Interactions

Stressing Bacteria to Death

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Science Signaling  14 Jun 2011:
Vol. 4, Issue 177, pp. ec164
DOI: 10.1126/scisignal.4177ec164

Peptidoglycan recognition proteins (PGRPs) are among the first defense against bacterial infection (see Kietzman and Tuomanen). They bind to a polymeric glycan present on the cell wall of all bacteria and trigger cell death. Kashyap et al. showed that three of the four mammalian PGRPs—PGLYRP-1, PGLYRP-3, and PGLYRP-4—and a dimer of PGLYRP-3 and PGLYRP-4 killed Gram-positive and Gram-negative bacteria through a mechanism dependent on the two-component system involved in sensing extracytoplasmic (between the membrane and cell wall) misfolded proteins. Several key observations led them to test the dependence of the bactericidal effect on the CssR-CssS two-component system in the Gram-positive Bacillis subtilis and the functionally homologous system CpxA-CpxR in the Gram-negative Escherichia coli. Exposure to the PGRPs inhibited cell wall synthesis without inhibiting the later steps in the process, transpeptidation and transglycosylation. PGRPs caused an inhibition of protein, DNA, and RNA synthesis at the same concentrations required for the bactericidal effect. The PGRPs failed to permeabilize the cell membranes but did trigger rapid and sustained membrane depolarization, which effectively abolishes adenosine triphosphate production because of loss of the proton gradient. Membrane depolarization was accompanied by an increase in intracellular toxic hydroxyl radicals, and chemicals that either blocked the production of the free radicals or scavenged them inhibited PGRP-mediated bacterial killing. These characteristics of loss of membrane potential, inhibition of molecular biosynthesis, and free radical production are also associated with the response to antibiotic-induced accumulation of misfolded proteins, which is mediated by the CpxA-CpxR system in E. coli. Indeed, B. subtilis deficient in CssR-CssS activity exhibited reduced membrane depolarization and free radical production in response to PGRP treatment and, in turn, were resistant to death in response to PGRP. E. coli with the analogous knockouts were also resistant to PGRP-mediated death. PGRPs triggered induction of a transcript responsive to the stress-sensing pathway mediated by CpxA-CpxR or CssR-CssS in E. coli and B. subtilis, respectively, confirming that the PGRPs activated the pathway. Thus, PGRPs trigger bacterial suicide by activating the two-component system that detects and responds to misfolded protein stress.

D. R. Kashyap, M. Wang, L.-H. Liu, G.-J. Boons, D. Gupta, R. Dziarski, Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems. Nat. Med. 17, 676–683 (2011). [PubMed]

C. Kietzman, E. Tuomanen, PGRPs kill with an ancient weapon. Nat. Med. 17, 665–666 (2011). [PubMed]

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