A Role of Lipophilic Peptidoglycan-related Molecules in Induction of Nod1-mediated Immune Responses

Mizuho Hasegawa,Akiko Kawasaki,Kangkang Yang,Yukari Fujimoto,Junya Masumoto,Eefjan Breukink,Gabriel Nuñez,Koichi Fukase,Naohiro Inohara

doi:10.1074/jbc.m700846200

Abstract

Nod1 is an intracellular protein that is involved in recognition of bacterial molecules and whose genetic variation has been linked to several inflammatory diseases. Previous studies suggested that the recognition core of Nod1 stimulatory molecules is gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP), but the identity of the major Nod1 stimulatory molecule produced by bacteria remains unknown. Here we show that bacteria produce lipophilic molecules capable of stimulating Nod1. Analysis of synthetic compounds revealed stereoselectivity of the DAP residue and that conjugation of lipophilic acyl residues specifically enhances the Nod1 stimulatory activity of the core iE-DAP. Furthermore, we demonstrate that lipophilic molecules induce and/or enhance the secretion of innate immune mediators from primary mouse mesothelial cells and human monocytic MonoMac6 cells, and this effect is mediated through Nod1. These results provide insight into the mechanism of immune recognition via Nod1, which might be useful in the design and testing of novel immunoregulators.

Highlights

The innate immune receptors recognize specific molecules that are commonly found in microbes and induce host defense responses to eliminate invading pathogens [1]
We demonstrate that lipophilic molecules induce and/or enhance the secretion of innate immune mediators from primary mouse mesothelial cells and human monocytic MonoMac6 cells, and this effect is mediated through Nod1
The iE-DAP structure is found in the insoluble fraction of intact PGN, intermediates of PGN synthesis and cleaved PGN products produced during bacterial growth and PGN recycling [11, 19], the identity of the major Nod1 stimulatory molecule (s) remains unknown [18]

Summary

Introduction

The innate immune receptors recognize specific molecules that are commonly found in microbes and induce host defense responses to eliminate invading pathogens [1]. Further analysis revealed that purified lipophilic iE-DAP-containing molecules possess both Nod1 and Nod2 stimulatory activity.

Results

Conclusion