Bacterial peptidoglycan degrading enzymes and their impact on host muropeptide detection

Abstract

Peptidoglycan (PGN) is a major component of the bacterial cell envelope in both Gram-positive and Gram-negative bacteria. These muropeptides can be produced or modified by the activity of bacterial glycolytic and peptidolytic enzymes referred to as PGN hydrolases and autolysins. Some of these bacterial enzymes are crucial for bacterial pathogenicity and have been shown to modulate muropeptide release and/or host innate immune responses. The ability of muropeptides to modulate host responses is due to the fact that eukaryotes do not produce PGN and have instead evolved numerous strategies to detect intact PGN and PGN fragments (muropeptides). Here we review the structure of PGN and introduce the various bacterial enzymes known to degrade or modify bacterial PGN. Host factors involved in PGN and muropeptide detection are also briefly discussed, as are examples of how specific bacterial pathogens use PGN degradation and modification to subvert host innate immunity.

Keywords: autolysin; bacteria; peptidoglycan; subversion.

Fig. 1

Structure of Lys-type and DAP-type PGN. a Lys-type PGN contains a lysine at the third position of the peptide stem and is predominantly seen in Gram-positive bacterial species. DAP-type PGN contains a mDAP at the third position of the peptide stem and is predominantly seen in Gram-negative bacterial species. Arrows indicate sites of PGN cleavage by PGN hydrolytic enzymes: 1 = N-acetylglucosaminidases; 2 = N-acetylmuramidases; 3 = N-acetylmuramyl-L-alanine amidases; 4 = glutamyl-mesodiaminopimelate endopeptidases of the p60/NLP family; 5 = other endopeptidases; 6 = carboxy- and trans-peptidases such as those of the penicillin-binding proteins (PBP) family. Lytic transglycosylases can also cleave between the sugar backbone moieties (1 and 2). b Biologically active PGN fragments (muropeptides) include tracheal cytotoxin (TCT), (glutamyl)-muramyldipeptide [(G)MDP] and (glutamyl)-muramyltetrapep-tide [(G)MTP]. (G)MDP triggers host Nod2 and NALP3 activation, while murine Nod1 detects both TCT and MTP.

Fig. 2

Pathogenic bacteria encode variable repertoires of ‘redundant’ PGN-hydrolyzing enzymes that may permit unique biological functions. a Considerable variation is seen in the numbers of PGN-hydrolyzing amidases and domain assortments within these enzymes between B. anthracis Sterne, M. tuberculosis H37Rv and L. monocytogenes EGDe. Shown are SLH domains, LGFP domains and PG-binding-1 domains, all of which are distinct putative PGN cell wall-binding domains. Variability in these domains may facilitate distinct binding or cleavage specificities for the various amidases, perhaps to target specific PGN substructures or muropeptides. Protein names listed are NCBI designations. b Domain structures of the 3 L. monocytogenes PGN hydrolases that contain a NlpC/p60 catalytic domain. SH3 is a proline-binding domain and LysM is a PGN-binding domain, while functions of the threonine-asparagine repeat region are unknown. These related enzymes appear to have distinct functions, since mutation of p60 in L. monocytogenes 10403S appears to uniquely reduce pathogenicity and host NK cell responses in infected animals.