NOD-Like Receptor Signaling in Innate Immunity

NOD-like receptors (NLRs) constitute a family of intracellular sensors fundamental to host defence. Central members, NOD1 and NOD2, detect specific peptidoglycan motifs derived from bacterial cell walls, triggering oligomerisation via their nucleotide-binding oligomerisation domains (NOD) and recruitment of the serine/threonine kinase RIPK2 through homotypic caspase recruitment domains (CARDs). Subsequent ubiquitylation of RIPK2 and engagement of adaptor proteins lead to activation of NF-κB and mitogen-activated protein kinase (MAPK) cascades. This promotes transcription of inflammatory cytokines, antimicrobial peptides and programmes of autophagy. Precise regulation of NLR signalling is vital: loss-of-function mutations predispose to inflammatory bowel disease, while gain-of-function variants underlie granulomatous disorders. Beyond bacterial recognition, NLRs have been implicated in antiviral responses, endoplasmic reticulum stress-induced inflammation and cell death pathways. Their centrality to pathogen clearance, tissue homeostasis and inflammatory pathology has driven efforts to elucidate structural mechanisms of activation and to develop targeted modulators with therapeutic potential.

Research from Nature Portfolio

High-resolution structural analysis of NOD2 in an ADP-bound closed conformation has revealed how nucleotide binding stabilises inter-domain interfaces and prevents premature oligomerisation. Mapping of disease-associated mutations onto this structure has illuminated divergent effects: variants linked to Blau syndrome destabilise inhibitory contacts to promote constitutive activation, whereas Crohn’s disease mutations disrupt ligand recognition and oligomer assembly. In parallel, development of a selective RIPK2 kinase inhibitor, WEHI-345, has demonstrated that transient delay of RIPK2 ubiquitylation is sufficient to abrogate pro-inflammatory cytokine production in vitro and to ameliorate autoimmune pathology in an experimental encephalomyelitis model. These findings underscore the critical role of RIPK2 enzymatic function in NOD signalling and validate kinase inhibition as a tractable strategy for treating autoinflammatory disorders.

NOD-Like Receptor Signaling in Innate Immunity publication trend

The graph below shows the total number of articles in nod-like receptor signaling in innate immunity across all publications each year (not limited to Nature Index journals).

Technical terms

NOD-like receptors (NLRs): Intracellular pattern-recognition receptors that detect microbial motifs or cell stress and initiate innate immune signalling.

CARD (Caspase Recruitment Domain): Protein interaction module that mediates homotypic binding between NLRs and downstream kinases such as RIPK2.

Oligomerisation: Assembly of multiple receptor molecules into a signalling platform upon activation.

Ubiquitylation: Covalent attachment of ubiquitin chains to a target protein, regulating its activity or stability.

NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells): Transcription factor complex central to inflammatory and immune gene expression.

MAPK (Mitogen-Activated Protein Kinase): Signalling cascade that transduces stress and cytokine signals to control gene expression and cell fate.

Peptidoglycan: Polymer forming the bacterial cell wall, composed of glycan strands cross-linked by peptide bridges; source of NOD ligands.

References

1. NOD2 reduces the chemoresistance of melanoma by inhibiting the TYMS/PLK1 signaling axis. Cell Death & Disease (2024).
2. Paired protein kinases PRKCI-RIPK2 promote pancreatic cancer growth and metastasis via enhancing NF-κB/JNK/ERK phosphorylation. Molecular Medicine (2023).
3. Multifaceted roles and regulation of nucleotide-binding oligomerization domain containing proteins. Frontiers in Immunology (2023).
4. Crystal structure of NOD2 and its implications in human disease. Nature Communications (2016).
5. A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production. Nature Communications (2015).