Nod-like-receptor
Encyclopedia
The NOD-like receptors in short for Nucleotide Oligomerization Domain receptors, are cytoplasmic proteins that may have a variety of functions in regulation of inflammatory
and apoptotic
responses. NLRs are encoded by genes from a large gene family
present in many different animal species; there are more than 20 NLR genes in human
s. Many are thought to serve as pattern recognition receptors (PRRs) which sense microbial products in the cytoplasm of cells, although some members have different functions. As such, it plays an important role in non-specific immunity.
), causing cleavage and activation of important inflammatory cytokine
s such as IL-1
. NLRs may also activate the NF-κB signaling pathway to induce production of inflammatory molecules.
transactivator (CIITA
) and NAIP
. The C of NLRC represents a caspase recruitment domain (CARD) these proteins possess at their N-terminus, while the P of NLRP represents a pyrin domain
.
and NLRC2
are known as NOD1 and NOD2, respectively. NLRC1 recognizes a molecule called Meso
-diaminopimelic acid
(meso-DAP), a peptidoglycan
constituent unique to Gram negative bacteria. NLRC2 proteins recognize intracellular MDP (muramyl dipeptide
), which is a peptidoglycan constituent of both Gram positive and Gram negative bacteria. Microbial product recognition is mediated by a C-terminal leucine-rich repeat
(LRR) region, while NLRCs initiate NF-κB and MAP kinase signaling cascades by interacting RIPK2
, a serine-threonine kinase, via their N-terminal CARD domain
. NLRC4
(IPAF) has also been shown to activate caspase-1 in response to bacteria.
s. NLRPs were previously known as NALPs. Interaction with other proteins (e.g., the adaptor molecule ASC
) is mediated via the N-terminal pyrin (PYD) domain. There are 14 members of this subfamily in humans (NLRP1 to NLRP14). NLRP3 mutations are responsible for the autoinflammatory diseases familial cold autoinflammatory syndrome, Muckle-Wells syndrome
and neonatal onset multisystem inflammatory disease
. Activators of NLRP3 include muramyl dipeptide
, bacterial DNA (non-methylated CpG repeats), ATP
, toxins, double stranded RNA
, paramyxovirus
es and uric acid
crystals. Although these specific molecules have been shown to activate NALP3, it remains unclear whether this is due to direct binding or due to cellular stress induced by these agents.
have also been shown to activate caspase-1 in response to Salmonella
and Legionella
.
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
responses. NLRs are encoded by genes from a large gene family
Gene family
A gene family is a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions...
present in many different animal species; there are more than 20 NLR genes in human
Human
Humans are the only living species in the Homo genus...
s. Many are thought to serve as pattern recognition receptors (PRRs) which sense microbial products in the cytoplasm of cells, although some members have different functions. As such, it plays an important role in non-specific immunity.
Nomenclature
New terminology for NOD-like receptors was adopted by the Human Genome Organization (HUGO) in 2008 to standardize the nomenclature of NLRs. The initialism NLR (for NOD-like receptor) was redefined to provide description of the families common features: "nucleotide-binding oligomerization domain, leucine rich repeat and ", then the functionally differentiating domain such as "CARD domain containing 3" for NLRC3. Past designations for NLRs include CATERPILLER (CLR), NOD, NALP, PAN and PYPAF.Function
NOD-like receptors may recognize endogenous or microbial molecules, perhaps including molecules produced in response to stress. They may then form oligomers that activate inflammatory caspases (e.g. caspase 1Caspase 1
Caspase 1 is an enzyme that proteolytically cleaves other proteins, such as the precursor forms of the inflammatory cytokines interleukin 1-β and interleukin 18, into active mature peptides...
), causing cleavage and activation of important inflammatory cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s such as IL-1
IL-1
IL-1 may refer to:* Interleukin 1, a protein* Illinois' 1st congressional district* Illinois Route 1* Building 1 of Infinite Loop , the Headquarters of Apple Inc....
. NLRs may also activate the NF-κB signaling pathway to induce production of inflammatory molecules.
Family members
Approximately 20 NLR proteins have been found in the mammalian genome. NLRs may be divided largely into two major subfamilies: the NLRCs (previously called NODs) and the NLRPs (previously called NALPs). Other NLRs include the MHC Class IIMHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
transactivator (CIITA
CIITA
CIITA is a human gene which encodes a protein called the class II, major histocompatibility complex, transactivator. Mutations in this gene are responsible for the bare lymphocyte syndrome in which the immune system is severely compromised and cannot effectively fight infection...
) and NAIP
NAIP
Baculoviral IAP repeat-containing protein 1 is a protein that in humans is encoded by the NAIP gene.-External links:...
. The C of NLRC represents a caspase recruitment domain (CARD) these proteins possess at their N-terminus, while the P of NLRP represents a pyrin domain
Pyrin domain
A pyrin domain is a protein domain and a subclass of protein motif known as the death fold; it allows a pyrin domain containing protein to interact with other proteins that contain a pyrin domain...
.
NLRC
NLRC1NOD1
Nucleotide-binding oligomerization domain-containing protein 1 is a protein receptor that in humans is encoded by the NOD1 gene. It recognizes bacterial molecules and stimulates an immune reaction....
and NLRC2
NOD2
Nucleotide-binding oligomerization domain-containing protein 2 also known as caspase recruitment domain-containing protein 15 or inflammatory bowel disease protein 1 is a protein that in humans is encoded by the NOD2 gene located on chromosome 16. NOD2 plays an important role in the immune system...
are known as NOD1 and NOD2, respectively. NLRC1 recognizes a molecule called Meso
Meso compound
A meso compound or meso isomer is a non-optically active member of a set of stereoisomers, at least two of which are optically active. This means that despite containing two or more stereocenters it is not chiral. A meso compound is superimposable on its mirror image, and it does not produce a ""...
-diaminopimelic acid
Diaminopimelic acid
Diaminopimelic acid is an amino acid, representing an epsilon-carboxy derivative of lysine.DAP is a characteristic of certain cell walls of some bacteria. When provided, they exhibit normal growth. When in deficiency, they still grow but with the inability to make new cell wall proteoglycan.This...
(meso-DAP), a peptidoglycan
Peptidoglycan
Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of bacteria , forming the cell wall. The sugar component consists of alternating residues of β- linked N-acetylglucosamine and N-acetylmuramic acid...
constituent unique to Gram negative bacteria. NLRC2 proteins recognize intracellular MDP (muramyl dipeptide
Muramyl dipeptide
Muramyl dipeptide is a peptidoglycan constituent of both Gram positive and Gram negative bacteria. It is composed of N-acetylmuramic acid linked by its lactic acid moiety to the N-terminus of an L-alanine D-isoglutamine dipeptide.-See also:* Dipeptide...
), which is a peptidoglycan constituent of both Gram positive and Gram negative bacteria. Microbial product recognition is mediated by a C-terminal leucine-rich repeat
Leucine-rich repeat
A leucine-rich repeat is a protein structural motif that forms an α/β horseshoe fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine...
(LRR) region, while NLRCs initiate NF-κB and MAP kinase signaling cascades by interacting RIPK2
RIPK2
Receptor-interacting serine/threonine-protein kinase 2 is an enzyme that in humans is encoded by the RIPK2 gene.-Further reading:...
, a serine-threonine kinase, via their N-terminal CARD domain
CARD domain
Caspase recruitment domains, or Caspase activation and recruitment domains , are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct...
. NLRC4
NLRC4
NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the NLRC4 gene.-Interactions:NLRC4 has been shown to interact with caspase 1 and NOD2.-Further reading:...
(IPAF) has also been shown to activate caspase-1 in response to bacteria.
NLRP
Like NLRCs, NLRPs contain C-terminal LRRs, which appear to act as regulatory domains and may be involved in the recognition of microbial pathogens, and a nucleotide binding site for nucleoside triphosphateNucleoside triphosphate
Nucleoside triphosphate is a nucleoside with three phosphates. Natural nucleoside triphosphates include adenosine triphosphate , guanosine triphosphate , cytidine triphosphate , 5-methyluridine triphosphate , and uridine triphosphate . These terms refer to those nucleoside triphosphates that...
s. NLRPs were previously known as NALPs. Interaction with other proteins (e.g., the adaptor molecule ASC
PYCARD
Apoptosis-associated speck-like protein containing a CARD or ASC is a protein that in humans is encoded by the PYCARD gene.This gene encodes an adaptor protein that is composed of two protein–protein interaction domains: a N-terminal PYRIN-PAAD-DAPIN domain and a C-terminal caspase-recruitment...
) is mediated via the N-terminal pyrin (PYD) domain. There are 14 members of this subfamily in humans (NLRP1 to NLRP14). NLRP3 mutations are responsible for the autoinflammatory diseases familial cold autoinflammatory syndrome, Muckle-Wells syndrome
Muckle-Wells syndrome
Muckle–Wells syndrome , also known as , is a rare autosomal dominant disease which causes sensorineural deafness, recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and painful joints. As a result, MWS is considered a type of periodic fever syndrome...
and neonatal onset multisystem inflammatory disease
Neonatal onset multisystem inflammatory disease
Neonatal onset multisystem inflammatory disease is a rare genetic periodic fever syndrome which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period...
. Activators of NLRP3 include muramyl dipeptide
Muramyl dipeptide
Muramyl dipeptide is a peptidoglycan constituent of both Gram positive and Gram negative bacteria. It is composed of N-acetylmuramic acid linked by its lactic acid moiety to the N-terminus of an L-alanine D-isoglutamine dipeptide.-See also:* Dipeptide...
, bacterial DNA (non-methylated CpG repeats), ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, toxins, double stranded RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
, paramyxovirus
Paramyxovirus
Paramyxoviruses are viruses of the Paramyxoviridae family of the Mononegavirales order; they are negative-sense single-stranded RNA viruses responsible for a number of human and animal diseases.-Genera:*Subfamily Paramyxovirinae**Genus Avulavirus Paramyxoviruses (from Greek para-, beyond, -myxo-,...
es and uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
crystals. Although these specific molecules have been shown to activate NALP3, it remains unclear whether this is due to direct binding or due to cellular stress induced by these agents.
Other NLRs
Other NLRs such as NAIPNAIP
Baculoviral IAP repeat-containing protein 1 is a protein that in humans is encoded by the NAIP gene.-External links:...
have also been shown to activate caspase-1 in response to Salmonella
Salmonella
Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...
and Legionella
Legionella
Legionella is a pathogenic Gram negative bacterium, including species that cause legionellosis or Legionnaires' disease, most notably L. pneumophila. It may be readily visualized with a silver stain....
.