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  • Review Article
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Signalling pathways and molecular interactions of NOD1 and NOD2

Nature Reviews Immunology volume 6, pages 9–20 (2006)Cite this article

Key Points

  • The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 are members of a recently described protein family, the NACHT (domain present in NAIP, CIITA, HET-E and TP1)-LRR (leucine-rich repeat) family (NLR family). Proteins in this family are structurally related cytosolic proteins with LRR domains (which bind microbial ligands) that are similar to those found in Toll-like receptors (TLRs). As such, NOD1 and NOD2 have important roles in innate immunity.

  • NOD1 and NOD2 are expressed by epithelial cells and antigen-presenting cells. Through their LRR domain, they recognize conserved components of the bacterial cell-wall constituent peptidoglyan: NOD1 binds γ-D-glutamyl-meso-diaminopimelic acid, and NOD2 binds muramyl dipeptide. Such recognition leads to the oligomerization of NOD1 and NOD2, followed by activation of the downstream effector molecule RICK (receptor-interacting serine/threonine kinase). This, in turn, leads to activation of nuclear factor-κB and other effector pathways.

  • The outcome of NOD2 signalling is complex. NOD2 can function as a mediator of innate immunity by itself, but it might also function as a modifier of innate immunity that results from TLR activity. So, there is evidence that NOD2 downregulates T-helper-1-cell responses (that is, interleukin-12 (IL-12) production) that are induced after peptidoglycan binds TLR2. By contrast, there is also evidence that NOD2 upregulates tumour-necrosis factor, IL-6 and CXC-chemokine ligand 8 (CXCL8; also known as IL-8) production induced by signalling through a broad range of TLRs.

  • Whereas NOD1 is broadly expressed by intestinal epithelial cells, NOD2 is expressed mainly by Paneth cells, which are located at the base of the epithelial crypts. In these cells, NOD2 might be an important inducer of α-defensins, which are antibacterial peptides that have a role in host defence at the epithelial interface.

  • Mutations in the LRR domain of the caspase-recruitment domain 15 gene (CARD15; which encodes NOD2) are associated with the development of Crohn's disease, whereas mutations in the NOD of NOD2 can lead to the development of Blau syndrome. On the basis of studies of mice that lack Card15 and mice with a mutated Card15 'knocked-in', three explanations for these associations are under consideration. In each case, the proposed mechanism leads to a dysregulated innate immune response to components of the microbial flora of the gut, so this highlights the normal role of NOD2 in mucosal homeostasis.

  • NOD1 is activated by microbial components that gain entry to the cytosol of epithelial cells. Such activation leads to the production of chemokines and possibly other host-defence factors against potential gut pathogens. So, mice with defective NOD1 function are more susceptible to infection with Helicobacter pylori, and NOD1 might be a factor in human diseases that involve this organism.

Abstract

The NOD (nucleotide-binding oligomerization domain) proteins NOD1 and NOD2 have important roles in innate immunity as sensors of microbial components derived from bacterial peptidoglycan. The importance of these molecules is underscored by the fact that mutations in the gene that encodes NOD2 occur in a subpopulation of patients with Crohn's disease, and NOD1 has also been shown to participate in host defence against infection with Helicobacter pylori. Here, we focus on the molecular interactions between these NOD proteins and other intracellular molecules to elucidate the mechanisms by which NOD1 and NOD2 contribute to the maintenance of mucosal homeostasis and the induction of mucosal inflammation.

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Figure 1: Structure and cellular location of TLRs and NOD1 and NOD2.
Figure 2: Signalling pathways of NOD1 and NOD2.
Figure 3: Models of the molecular interactions between TLR- and NOD2-signalling pathways in antigen-presenting cells.
Figure 4: Possible mechanisms of Crohn's disease in patients with mutations in CARD15.

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Acknowledgements

We thank T. Chiba (Department of Gastroenterology, Kyoto University Graduate School of Medicine, Kyoto, Japan) for helpful discussions. Work in the laboratory of P.J.M. is supported by the National Institutes of Health (United States) and by the American Lebanese Syrian Associated Charities, Inc.

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Authors and Affiliations

  1. Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10 CRC, 5W3940, 10 Center Drive, Bethesda, 20892, Maryland, USA

    Warren Strober, Atsushi Kitani & Tomohiro Watanabe

  2. Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, 38105, Tennessee, USA

    Peter J. Murray

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  1. Warren Strober
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Glossary

LRR domain

(leucine-rich-repeat domain). A domain that mediates the detection of ligands derived from microbial components. The LRR domain of NLRs (NACHT-LRR proteins) is similar to that of Toll-like receptors. It consists of leucine-rich amino-acid strands forming a peptide loop. The loops occur as tandem repeats that, together, form a coil or 'solenoid' and contain constant sequences, as well as unique 'insertions' or variable residues for each ligand.

NOD

(nucleotide-binding oligomerization domain). The domain that defines NLRs (NACHT-LRR proteins). Its most characteristic feature is that it contains sequences that, on binding of ligand to the leucine-rich repeat (LRR) domain, facilitate self-oligomerization, and it also has ATPase activity. This oligomerization might be a key activation event that allows NLRs to bind to, and activate, downstream effector molecules through their caspase-recruitment domain or pyrin domain.

CARD or pyrin domain

(caspase-recruitment domain or pyrin domain). The amino-terminal effector-binding domain of NLRs (NACHT-LRR proteins) usually consists of a CARD or a pyrin cassette for promoting molecular interactions. Proteins that contain a pyrin or CARD cassette in this region are also known as NALPs (NACHT-, LRR- and pyrin-domain-containing proteins) or nucleotide-binding oligomerization domain (NOD) proteins, respectively.

Type IV secretion system

A type of molecular syringe of Gram-negative bacteria. It enables the bacteria to deliver DNA (delivered by species such as Agrobacterium spp.) and protein effectors (delivered by species such as Helicobacter pylori) into eukaryotic cells.

Pathogenicity island

The genetic element, the 'island of evil', in the genome of an organism that is responsible for the capacity of the organism to cause disease (that is, its pathogenicity). The virulence of the organism is modulated by genes harboured on this island.

K63-linked polyubiquitylation

Ubiquitylation that involves polyubiquitin chains linked through the lysine residue at position 63 of ubiquitin.

Dextran-sulphate-sodium-salt-induced colitis

(DSS-induced colitis). An animal model of colitis induced by administration of DSS in the drinking water. DSS changes epithelial-cell barrier function and creates a condition in which antigen-presenting cells or epithelial cells in the gut are exposed to mucosal microflora.

Adherent invasive E. coli

A type of Escherichia coli that has the ability to adhere to intestinal epithelial cells, to invade epithelial cells through a mechanism involving actin polymerization and microtubules, and to survive and replicate within macrophages.

Blau syndrome

A rare, autosomal dominant disorder that is characterized by granulomatous arthritis, uveitis, skin rash and cranial neuropathy.

Early-onset sarcoidosis

A rare disease that usually manifests in children younger than 4 years of age. This disease is characterized by non-caseating epithelioid granulomas in the skin, joints and eyes. Unlike typical sarcoidosis seen in adults, pulmonary involvement is not observed.

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Strober, W., Murray, P., Kitani, A. et al. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 6, 9–20 (2006). https://doi.org/10.1038/nri1747

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