Therapeutic targeting of NOD1 receptors

Abstract

The nucleotide-binding oligomerization domain 1 (NOD1) protein is an intracellular receptor for breakdown products of peptidoglycan (PGN), an essential bacterial cell wall component. NOD1 responds to γ-D-glutamyl-meso-diaminopimelic acid, which is an epitope unique to PGN structures from all Gram-negative bacteria and certain Gram-positive bacteria. Upon ligand recognition, NOD1 undergoes conformational changes and self-oligomerization mediated by the nucleotide-binding NACHT domains, followed by the recruitment and activation of the serine threonine kinase receptor-interacting protein 2 leading to the activation of NF-κB and MAPK pathways and induction of inflammatory genes. Much of our knowledge is derived from seminal studies using mice deficient in NOD1 and confirming an essential role for NOD1 in the host immune response against gastrointestinal and respiratory pathogens. In addition, recent studies have revealed a role for intracellular NOD1 receptors in the regulation of vascular inflammation and metabolism. This review will discuss our current understanding of intracellular NOD1 receptors in host immunity and chronic inflammatory disorders with a focus on cardiovascular diseases. Although therapeutic advances may have to wait until the complex interplay with pathogens, danger signals, other pattern recognition receptors and overlapping metabolic pathways is further unravelled, the steadily growing body of knowledge suggest that NOD1 antagonism might represent attractive candidate to reduce excessive inflammation associated to intestinal, cardiovascular and metabolic diseases.

Keywords: atherosclerosis; endothelium; intestinal immunity; metabolic syndrome; pulmonary immunity; receptor-interacting protein 2; septic shock.

Figure 1

NOD1 signalling via RIP2. Recognition of meso-DAP (iE-DAP) through LRR domains activates the NOD1 protein, which then associates with RIP2 via CARD–CARD interactions. Subsequent K63-linked polyubiquitination at K209 in RIP2 allows for recruitment of the TAK1/TAK1-binding protein (TAB1, 2, 3) complex, which leads to interaction with the NF-κB inhibitor NEMO and release of NF-κB to initiate gene transcription. TAK1 is also required for the activation of the MAPK pathways. K47 and K209, lysine residues at RIP2; KD, kinase domain; LRR, leucine-rich repeat; TAK1, TGF-β-activated kinase. Adapted from Hasegawa et al., .

Figure 2

Therapeutic potential of NOD1 modulation. The most promising and clear use of NOD1 agonists is as adjuvants for the treatment of microbial infections not responding well to antibiotics, particularly for gastrointestinal and respiratory infections. In addition, the growing body of research suggest that NOD1 modulation may open a new lead for the development of more selective anti-inflammatory drug targeting when attempting to reduce collateral damage from the septic immune response. Finally, NOD1 activation has been linked to a number of chronic inflammatory diseases suggesting that NOD1 antagonists represent attractive candidates to reduce excessive inflammation associated to intestinal, cardiovascular and metabolic diseases. IBD, inflammatory bowel disease.