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Cell death and immunity

NODs: intracellular proteins involved in inflammation and apoptosis

Key Points

  • The family of NOD proteins includes the apoptosis regulator APAF1 (apoptotic protease activating factor 1) and up to 25 NOD-LRR proteins, some of which have been implicated in the regulation of inflammatory responses.

  • Most NOD proteins are comprised of three distinct functional domains: an amino-terminal effector-binding domain (EBD), a centrally located nucleotide-binding oligomerization domain (NOD) and a carboxy-terminal ligand-recognition domain (LRD).

  • The EBD of NOD-family members is highly diverse but most NOD proteins contain caspase-recruitment domains (CARDs) or pyrin domains (PYDs). With the exception of APAF1, all mammalian NOD proteins contain leucine-rich repeats (LRRs) as LRDs.

  • Two NOD proteins, NOD1 and NOD2, recognize bacterial components through their LRRs and mediate the activation of nuclear factor-κB (NF-κB) through the downstream effector RICK. NOD2 recognizes muramyl dipeptide, a conserved structure in bacterial peptidoglycan.

  • Many NOD proteins, including APAF1, NOD1, NOD2, death effector filament-forming CED-4-like apoptosis protein (DEFCAP), ICE-protease activating factor (IPAF) and cryopyrin, have been shown to induce or enhance apoptosis.

  • Several NOD proteins, including IPAF and cryopyrin, associate with ASC, an adaptor molecule containing a CARD and a PYD. Oligomerization of cryopyrin and IPAF mediates NF-κB and caspase activation through ASC.

  • Genetic variation of three human NOD proteins — NOD2, cryopyrin and MHC class II transactivator (CIITA) — has been implicated in inflammatory disease and/or immunodeficiency. Genetic variation in neuronal apoptosis inhibitory protein (NAIP) has been shown to affect intracellular replication of Legionella pneumophila in mice.

Abstract

NOD (nucleotide-binding oligomerization domain) proteins are members of a family that includes the apoptosis regulator APAF1 (apoptotic protease activating factor 1), mammalian NOD-LRR (leucine-rich repeat) proteins and plant disease-resistance gene products. Several NOD proteins have been implicated in the induction of nuclear factor-κB (NF-κB) activity and in the activation of caspases. Two members of the NOD family, NOD1 and NOD2, mediate the recognition of specific bacterial components. Notably, genetic variation in the genes encoding the NOD proteins NOD2, cryopyrin and CIITA (MHC class II transactivator) in humans and Naip5 (neuronal apoptosis inhibitory protein 5) in mice is associated with inflammatory disease or increased susceptibility to bacterial infections. Mammalian NOD proteins seem to function as cytosolic sensors for the induction of apoptosis, as well as for innate recognition of microorganisms and regulation of inflammatory responses.

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Figure 1: Induced proximity model of NOD protein activation.
Figure 2: Signalling pathways mediated by NOD1, NOD2, IPAF and cryopyrin.
Figure 3: Model for the role of NOD1, NOD2 and related NOD proteins in innate and adaptive immunity.
Figure 4: Hypothetical mechanisms of disease in patients with mutations in the genes encoding NOD2, cryopyrin, CIITA and pyrin.

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Acknowledgements

Work in our laboratories is supported by grants from the National Institutes of Health and Crohn's and Colitis Foundation of America.

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Authors and Affiliations

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Correspondence to Gabriel Nuñez.

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DATABASES

LocusLink

APAF1

ASC

caspase-3

caspase-9

CED-3

CED-4

CIITA

cryopyrin

DEFCAP

DIABLO/SMAC

IPAF

MATER

NAIP

NALP2

NEMO

NF-κB

NOD1

NOD2

NOD27

PAN2

PKR

PYPAF3

PYPAF5

PYPAF6

PYPAF7

RICK

OMIM

Bare lymphocyte syndrome

Blau syndrome

Crohn's disease

familial Mediterranean fever

FURTHER INFORMATION

Naohiro Inohara's website

Glossary

TOLL-LIKE RECEPTORS

(TLRs). These are membrane-bound proteins that have evolved to recognize common products that are unique to microbial agents. For example, TLR2, TLR3, TLR4, TLR5 and TLR9 are involved in the recognition of bacterial lipoproteins, viral double-stranded RNA, bacterial lipopolysaccharides, bacterial flagellin and bacterial CpG DNA, respectively.

CASPASES

A family of cysteine proteases that are involved in apoptosis and inflammation. Caspases are highly specific for certain protein substrates. For example, caspase-1 processes pro-interleukin-1β (IL-1β) into active IL-1β. Caspases are synthesized in the cell as inactive precursors and are activated by proteolytic processing. Certain caspases, including caspase-1, -8 and -9, have long prodomains containing death-effector domains (DEDs) or caspase-recruitment domains (CARDs). These DEDs and CARDs physically connect the caspases with crucial regulatory molecules through homophilic interactions.

SMAC

Second mitochondria-derived activator of caspase (SMAC), also known as DIABLO is a mitochondrial pro-apoptotic protein that is released during apoptosis together with cytochrome c and other pro-apoptotic factors. In the cytosol, active SMAC binds to inhibitor of apoptosis (IAP) proteins and disrupts the ability of the IAPs to inhibit caspases.

THE SPECK

A punctuated cytosolic structure that is formed in apoptotic cells or in cells that are transiently transfected with ASC (apoptosis-associated speck-like protein containing a CARD)-producing plasmids. The speck is thought to contain many proteins, including ASC.

DOMINANT-NEGATIVE MUTANTS

Mutant forms that interfere specifically with the function of the endogenous wild-type protein.

DANGER SIGNALS

Cell-wall components and other products of pathogens that alert the innate immune system to the presence of potentially harmful invaders, usually by interacting with Toll-like receptors and other pattern recognition receptors that are expressed by tissue cells and dendritic cells, for example.

COMPOUND HETEROZYGOCITY

Compound heterozygous individuals have different mutations of the same gene in each chromosome. By contrast, homozygotes have two identical copies of the same mutation.

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Inohara, N., Nuñez, G. NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3, 371–382 (2003). https://doi.org/10.1038/nri1086

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