Detection of enteric pathogens by the nodosome

Abstract

Nucleotide-binding oligomerization domain protein (NOD)1 and NOD2 participate in signaling pathways that detect pathogen-induced processes, such as the presence of peptidoglycan fragments in the host cell cytosol, as danger signals. Recent work suggests that peptidoglycan fragments activate NOD1 indirectly, through activation of the small Rho GTPase Ras-related C3 botulinum toxin substrate 1 (RAC1). Excessive activation of small Rho GTPases by virulence factors of enteric pathogens also triggers the NOD1 signaling pathway. Many enteric pathogens use virulence factors that alter the activation state of small Rho GTPases, thereby manipulating the host cell cytoskeleton of intestinal epithelial cells to promote bacterial attachment or entry. These data suggest that the NOD1 signaling pathway in intestinal epithelial cells provides an important sentinel function for detecting 'breaking and entering' by enteric pathogens.

Keywords: Nod-like receptors; pathogen detection; patterns of pathogenesis; type III secretions system.

Figure 1

Model for activation of the Nucleotide-binding oligomerization domain protein (NOD)1 nodosome in epithelial cells by diaminopimelic acid-type peptidoglycan or bacterial virulence factors, which requires excessive or prolonged activation of small Rho GTPases. Peptidoglycan (blue box) or bacterial virulence factors (blue circles) engage host proteins (red circles) to activate (arrows) the nodosome, thereby inducing the expression of proinflammatory genes. AP-1, activator protein-1; CDC42, cell division control protein 42 homolog; CNF1, cytotoxic necrotizing factor 1; DOCK, dedicator of cytokinesis; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; Fn, fibronectin; GEF, guanosine nucleotide-exchange factor; HSP90, heat shock protein 90; IκB, nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor; Iκk, I kB kinase; JNK, C-Jun N-terminal kinase; NEMO, NF-κB essential modulator; NF-κB, nuclear factor-κB; PI3, phosphoinositide 3; PIP, phosphatidylinositol phosphate; RAC1, Ras-related C3 botulinum toxin substrate 1; RHOA, Ras homolog gene family member A; RIP, receptor-interacting protein; SGT1, suppressor of G-two allele of Skp1; SspH2, Salmonella secreted protein H2; TIAM-1, T cell lymphoma invasion and metastasis-1.