Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems

Des Raj Kashyap et al. NATURE MEDICINE, 17: 676-683, 2011

Speaker: Chung-Han Hsieh (謝宗翰)                           Time: 15:00~16:00, Oct. 26, 2011

Commentator: Dr. Ching-Hao Teng (鄧景浩博士)      Place: Room 601

Abstract:

The mammalian peptidoglycan recognition proteins (PGRPs), like the antimicrobial lectins, can bind the bacterial cell wall and kill the bacteria. The authors found that these proteins enter the gram-positive bacteria cell wall at the daughter cell separation site, but they cannot enter the cytoplasm. They suspected that PGRPs may kill the bacterial cell by inhibiting an intracellular step of peptidoglycan synthesis. They then found that the synthesis of not only peptidoglycan but also DNA, RNA and protein was inhibited by PGRPs binding. These phenomena were caused by loss of the membrane potential, and the increased production of [OH]•. It has been demonstrated previously that the CpxA-CpxR two-component system in E. coli could detect the misfolded proteins in the antibiotics-treated bacterial cell and is responsible for membrane depolarization, stress response, [OH]• production and killing of the bacterial cell. A functionally homologous two-component system, CssR-CssS, was also found in B. subtilis. Deletion of the CssR-CssS or CpxA-CpxR system significantly raised the survival rate of PGRPs-treated B. Subtilis or E. coli. These findings together show that when PGRPs bind the vicinity of separation sites in a bacterial cell, the CssR-CssS and CpxA-CpxR two-component systems detect the signals and respond to result in membrane depolarization and [OH]• production, which lead to killing of the bacterial cell. This research has discovered a new target of antimicrobial drug development.

References:

1.      Dziarski Roman. Peptidoglycan recognition proteins (PGRPs). Molecular Immunology 40 (2004) 877–886

2.      Royet, J. and Dziarski, R. Peptidoglycan recognition proteins: pleiotropic sensors and effectors of antimicrobial defenses. Nat. Rev. Microbiol. 5, 264–277 (2007).

3.      Wang, Z.M. et al. Human peptidoglycan recognition protein-L is an N-acetylmuramoyl-l-alanine amidase., J. Biol. Chem. 278, 49044–49052 (2003).