Peptidoglycan recognition proteins (PGRPs or PGLYRPs) are innate immunity molecules that contain a conserved peptidoglycan-binding type 2 amidase domain that is homologous to bacteriophage and bacterial type 2 amidases (Kang D et al. 1998; Liu C et al. 2001; Royet J and Dziarski R 2007; Royet J et al. 2011; Dziarski R et al. 2016). Mammals have a family of four PGRPs (PGLYRP1, 2, 3 & 4) that are differentially expressed in a cell‑type‑ or tissue‑specific manner. Human PGLYRP1 (also known as PGRP‑S) is constitutively expressed primarily in polymorphonuclear (PMN) cell granules and functions as disulfide‑linked homodimers (Liu C et al. 2000, 2001; Cho JH et al. 2005; Guan R et al. 2005; Lu X et al. 2006; De Marzi MC et al. 2015). PGLYRP1 has a Zn(2+)-dependent bactericidal activity against both Gram-positive and Gram-negative bacteria at physiologic Zn(2+) concentrations found in the body fluids (Lu X et al. 2006; Wang M et al. 2007). PGLYRP1 is also active against Chlamydia trachomatis (Bobrovsky P et al. 2016). Killing of both Gram-positive and Gram-negative bacteria by PGLYRP1 is synergistically enhanced by antimicrobial peptides (phospholipase A2, alpha- and beta-defensins, and bactericidal permeability-increasing protein (BPI)) (Wang M et al. 2007), and also by lysozyme (Cho JH et al. 2005). The bactericidal activity of PGRPs requires their N-glycosylation, because deglycosylation with N-glycosidase abolished the bactericidal activity of these PGRPs for Bacillus subtilis, Staphylococcus aureus, and Escherichia coli (Lu X et al. 2006; Wang M et al. 2007).
PGRPs are thought to kill bacteria by interacting with cell wall peptidoglycan and by inducing lethal stress response in bacteria, rather than a hydrolysis of peptidoglycan or permeabilizing bacterial membranes as other antibacterial peptides do (Lu X et al. 2006; Wang M et al. 2007; Cho S et al. 2007; Kashyap DR et al. 2011, 2014). In Gram-positive bacteria, including B. subtilis, PGLYRP1, 3 & 4 were found to enter cell wall at the site of daughter cell separation during cell division and to bind to cell wall peptidoglycan in the vicinity of cell membrane (Kashyap DR et al. 2011). However, this binding did not inhibit the extracellular transglycosylation or transpeptidation steps in peptidoglycan synthesis (Kashyap DR et al. 2011), which are well-known targets for bactericidal antibiotics. Instead, this interaction of PGRP proteins and peptidoglycan activated the B. subtilis envelope stress response CssR‑CssS two-component system that detects and disposes of misfolded proteins exported out of bacterial cells. This activation resulted in bacterial membrane depolarization, cessation of intracellular peptidoglycan, protein, RNA, and DNA synthesis, and production of toxic hydroxyl radicals, which were responsible for bacterial death (Kashyap DR et al. 2011). PGRPs were shown to kill Gram-negative bacteria (E. coli) by binding to their outer membrane and activating the functionally homologous CpxA-CpxR two‑component system (Kashyap DR et al. 2011). Furthermore, genome expression arrays, qRT-PCR, and biochemical tests showed that PGRPs kill both E. coli and B. subtilis by inducing oxidative, thiol, and metal stress (Kashyap DR et al. 2014).
There is also emerging evidence that PGLYRP1 can function as a receptor agonist or antagonist for human cells. Human PGLYRP1 (multimerized or complexed with peptidoglycan) binds to and stimulates triggering receptor expressed on myeloid cells-1 (TREM-1), a receptor present on neutrophils, monocytes and macrophages that induces production of pro-inflammatory cytokines (Read CB et al. 2015). Moreover, PGLYRP1 and its complex with 70-kDa heat shock protein (Hsp70) bind to the tumor necrosis factor receptor-1 (TNFR1, which is a death receptor). The PGLYRP1-Hsp70 complex induces a cytotoxic effect via apoptosis and necroptosis (Yashin DV et al. 2015, 2016), which accounts for the tumor cytotoxicity of PGLYRP1-Hsp70 complexes secreted by cytotoxic lymphocytes (Sashchenko LP et al. 2004). By contrast, free PGLYRP1 acts as a TNFR1 antagonist, by binding to TNFR1 and inhibiting its activation by PGLYRP1-Hsp70 complexes.