title: Modification of the structure of peptidoglycan is a strategy to avoid detection by nucleotide-binding oligomerization domain protein 1.
abstract: Nucleotide-binding oligomerization domain (NOD) protein 1 (NOD1) and NOD2 are pathogen recognition receptors that sense breakdown products of peptidoglycan (PGN) (muropeptides). It is shown that a number of these muropeptides can induce tumor necrosis factor alpha (TNF-alpha) gene expression without significant TNF-alpha translation. This translation block is lifted when the muropeptides are coincubated with lipopolysaccharide (LPS), thereby accounting for an apparently synergistic effect of the muropeptides with LPS on TNF-alpha protein production. The compounds that induced synergistic effects were also able to activate NF-kappaB in a NOD1- or NOD2-dependent manner, implicating these proteins in synergistic TNF-alpha secretion. It was found that a diaminopimelic acid (DAP)-containing muramyl tetrapeptide could activate NF-kappaB in a NOD1-dependent manner, demonstrating that an exposed DAP is not essential for NOD1 sensing. The activity was lost when the alpha-carboxylic acid of iso-glutamic acid was modified as an amide. However, agonists of NOD2, such as muramyl dipeptide and lysine-containing muramyl tripeptides, were not affected by amidation of the alpha-carboxylic acid of iso-glutamic acid. Many pathogens modify the alpha-carboxylic acid of iso-glutamic acid of PGN, and thus it appears this is a strategy to avoid recognition by the host innate immune system. This type of immune evasion is in particular relevant for NOD1.
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA.
authors.forename: Margreet A
authors.initials: MA
authors.lastname: Wolfert
authors.forename: Abhijit
authors.initials: A
authors.lastname: Roychowdhury
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Boons
mesh_terms: D002460:Cell Line; D003960:Diaminopimelic Acid / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D015394:Molecular Structure; D016328:NF-kappa B / Q000032:analysis; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D010457:Peptidoglycan / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003960:Diaminopimelic Acid