Peptidoglycan Recognition Proteins Are a New Class of Human Bactericidal Proteins

Roman Dziarski,Xiaofeng Lu,Xinna Li,Haitao Wang,Dipika Gupta,Jin Qi,Minhui Wang

doi:10.1074/jbc.m511631200

Abstract

Skin and mucous membranes come in contact with external environment and protect tissues from infections by producing antimicrobial peptides. We report that human peptidoglycan recognition proteins 3 and 4 (PGLYRP3 and PGLYRP4) are secreted as 89-115-kDa disulfide-linked homo- and heterodimers and are bactericidal against several pathogenic and nonpathogenic transient, but not normal flora, Gram-positive bacteria. PGLYRP3 and PGLYRP4 are also bacteriostatic toward all other tested bacteria, which include Gram-negative bacteria and normal flora Gram-positive bacteria. PGLYRP3 and PGLYRP4 are also active in vivo and protect mice against experimental lung infection. In contrast to antimicrobial peptides, PGLYRPs kill bacteria by interacting with their cell wall peptidoglycan, rather than permeabilizing their membranes. PGLYRP3 and PGLYRP4 are expressed in the skin, eyes, salivary glands, throat, tongue, esophagus, stomach, and intestine. Thus, we have identified the function of mammalian PGLYRP3 and PGLYRP4, and show that they are a new class of bactericidal and bacteriostatic proteins that have different structures, mechanism of actions, and expression patterns than antimicrobial peptides.

Highlights

Peptidoglycan recognition proteins (PGRPs)3 are a family of innate immunity pattern recognition molecules that were first discovered in insects [15,16,17] and in mammals [16, 18, 19]
Bactericidal Activity of PGLYRP1, PGLYRP3, and PGLYRP4—Human PGLYRP1, PGLYRP3, and PGLYRP4 were secreted into the medium primarily as disulfide-linked homodimers, and cells that were cotransfected with human PGLYRP3 and PGLYRP4 exclusively secreted disulfide-linked PGLYRP3:4 heterodimers (Fig. 1A)
Co-expression of both PGLYRP3 and PGLYRP4 in the same cells was required for the formation of heterodimers, because mixing of PGLYRP3 and PGLYRP4 individually expressed in separate cells or mixing of cells separately transfected with PGLYRP3 and PGLYRP4 did not result in formation of heterodimers

Summary

Introduction

Peptidoglycan recognition proteins (PGRPs) are a family of innate immunity pattern recognition molecules that were first discovered in insects [15,16,17] and in mammals [16, 18, 19]. Mammals have a family of 4 PGRPs, which were initially named PGRP-S, PGRP-L, and PGRP-I␣ and PGRP-I␤ [18], but recently, the Human Genome Organization Gene Nomenclature Committee changed their names to peptidoglycan recognition proteins 1, 2, 3, and 4 (PGLYRP1, PGLYRP2, PGLYRP3, and PGLYRP4), respectively. Mammalian PGLYRP1 is present in granulocyte granules and likely participates in killing of phagocytized bacteria [31,32,33], and PGLYRP2 is an N-acetylmuramoyl-L-alanine amidase (34 –36), an enzyme that cleaves the stem peptide from the glycan chain of peptidoglycan and is constitutively produced in the liver and secreted into the bloodstream [18, 35, 36]. Because the function of mammalian PGLYRP3 and PGLYRP4 has been unknown, here we have identified their function by testing the hypothesis that human PGLYRP3 and PGLYRP4 (and PGLYRP1) have bactericidal activity and are expressed in tissues that come in contact with the external environment

Methods

Results

Conclusion