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NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of
NOD-like receptor The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs) (also known as nucleotide-binding leucine-rich repeat receptors), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the ...
. NOD-like receptors are a type of
pattern recognition receptor Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...
that are found in the cytosol of the cell, recognizing signals of antigens in the cell. NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or
pathogen-associated molecular pattern Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast arra ...
s, such as such as
peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ...
, which is found on some bacterial cells. It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the
inflammasome Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
, including K+ efflux and
caspase 1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...
activation. NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. As of now, there are at least 14 different known NLRP genes in humans, which are named NLRP1 through NLRP14. The genes translate into proteins with differing lengths of leucine-rich repeat domains.


Function

NLRP plays a key role in inflammation. It is a
scaffolding protein In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them in ...
and is crucial for aggregating other proteins that form the inflammasome. NLRP1, 3, 6, 7, and 12 are known to be involved in the formation of inflammasomes. NOD-like receptors, in general, activate
caspase-1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolysis, proteolytically cleaves other proteins, such as the Protein precursor, precursors of the inflammatory cytokines Interleukin 1 beta, interleuki ...
and assist in the maturation of the proinflammatory cytokines
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
and IL-18. However, not every NLRP forms an inflammasome and activates caspase-1; these NLRPs are referred to as non-canonical NLRPs. As with other NOD-like receptors, NLRPs function to recognize danger signals, which consist of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), which are present when tissue is damaged or under stress. NRLP3, which is well studied relative to the other NLRP genes, has been observed to play a significant role propagating immune response to aluminum in
adjuvants In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy#Pharmacology, efficacy or Potency (pharmacology), potency of certain drugs. Specifically, the term can refer to: * Adju ...
. NLRP3 is involved in the immune response to toxins in the environment. For example, NLRP3 is activated to form an inflammasome when liver cells are exposed to DBP, a chemical used in plastic toys and food packaging. Similar to its response to toxins, NLRP3 also plays a role in the inflammation that follows exposure to various allergens, thus leading to the activation of T helper 2 cells, which are responsible for the activation of allergic reactions. Many NLRPs regulate the activation of
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
, which is a transcription factor that leads to the production of various pro-inflammatory cytokines, such as IL-1 and
TNF-α Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
. For example, NLRP11, NLRP5, NLRP2, and NLRP12 have been shown to inhibit different steps in the NF-κB pathway, while there are other NLRPs that activate the pathway. Some NLRPs are thought to be maternal-effect genes, which are genes present in the developing egg and contribute to the early growth of an embryo. Specific NLRPs are highly expressed at certain points during embryo development and play different proles. NLRP5, for example, is a part of the human subcortical maternal complex, which is needed for the growth of the
zygote A zygote (, ) is a eukaryotic cell formed by a fertilization event between two gametes. The zygote's genome is a combination of the DNA in each gamete, and contains all of the genetic information of a new individual organism. In multicellula ...
in the early stages of cell division.


Structure

NLRP protein structure has a N-terminal PYD domain followed by
NACHT domain The NACHT domain is an evolutionarily conserved protein domain. This NTPase domain is found in apoptosis proteins as well as those involved in MHC transcription. Its name reflects some of the proteins that contain it: NAIP (NLP family apop ...
and several
leucine-rich repeats A leucine-rich repeat (LRR) 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. These tandem repeats commo ...
(LRR). These PYD domains can interact with other PYD domains to allow for interaction between NRLP and other proteins also containing a PYD domain. Pyrin domains recruit the scaffold protein that activates the inflammasome.


Expression

NLRPs are expressed in various parts of the body. These receptors are expressed in
white blood cell White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...
s, aiding the inflammation process upon activation by pathogen-associated molecular patterns, toxins, etc. NLRPs are also expressed in many other locations in humans. For example, NLRP1 was found in the
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s of the brain, including pyramidal cells. NLRP1 is also expressed in the
oligodendrocyte Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...
s, which are cells in the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
that myelinate neurons. NLRP1 has many alleles across the population, making it a very polymorphic gene. NLRP6 is highly expressed in the intestine and is involved in fighting viral intestinal infections. A number of NLRPs, such as NLRP10, NLRP3, and NLRP1, are expressed in the
keratinocyte Keratinocytes are the primary type of Cell (biology), cell found in the epidermis (skin), epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the stratum basale, basal layer (''str ...
s, or the keratin-producing cells in the epidermis. NLRP10 prevents inflammation in the skin, while NLRP1 and 3 activate the inflammasome. In humans, the exposure to UVB rays can activate NLRP1, leading to sunburn.


NRLP gene

In humans, NLRPs are primarily found on two chromosomes: 11p15, which contains NLRP6, 10, and 14, and 19q13.4, which contains the rest of the NLRP genes, excluding NLRP1 and 3. The majority of the NLRPs that are associated with reproduction, many of which are maternal-effect genes, are found on chromosome 19, excluding NLRP14. NLRP1 and NLRP3 are found on chromosomes 17p13.2 and 1q44, respectively.


Associated diseases

Many of the diseases known to be associated with NLRPs are due to NLRP3. For example, Muckle-Wells syndrome (MWS), Familial Cold Autoinflammatory syndrome (FCAS), and Chronic Infantile Neurological Cutaneous Articular syndrome (CINCA) are all consequences of mutations in the NLRP3 gene. The pathology of these diseases involves the increase in the release of IL-1, leading to inflammation. NLRP3 has also been implicated in the development of diseases such as
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
,
inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...
, and
gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intensit ...
. Both NLRP1 and NLRP3 are involved in neurodegeneration.
Amyloid beta Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...
aggregation and oligomerization, which is found in individuals with
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, activates the inflammasomes from NLRP1 and 3. Caspase activity that is triggered by the NLRP1 inflammasome activates caspase-6, which destroys the axons of neurons.


Role in plants

Plants also recognize danger signals, and it is thought that plants utilize receptors similar to NLRPs to detect these signals. Plant nod-like receptors, however, differ from human NLRs in that some of the domains of the protein are different. For example, the pyrin domain of NLRPs is replaced by either a coiled-coil domain or a toll and interleukin receptor. Likewise, the NACHT domain in human NLRs is instead the nucleotide binding domain in the plant NLR.


Genes

Some NLRP genes code for a series of NACHT, LRR and PYD domains-containing proteins, including: *
NLRP1 NLRP1 encodes NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1 in humans. NLRP1 was the first protein shown to form an inflammasome. Material was copied from this source, which is available under Creative Commons Attribution 4. ...
, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 1 *
NLRP2 NACHT, LRR and PYD domains-containing protein 2 is a protein that in humans is encoded by the ''NLRP2'' gene. NALP proteins, such as NALP2, are characterized by an N-terminal pyrin domain (PYD) and are involved in the activation of caspase-1 (C ...
, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 2 *
NLRP3 NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1. NLRP3 is ...
, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 3 *
NLRP4 NACHT, LRR and PYD domains-containing protein 4 is a protein that in humans is encoded by the ''NLRP4'' gene. NALPs are cytoplasmic proteins that form a subfamily within the larger CATERPILLER protein family. Most short NALPs, such as NALP4, hav ...
, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 4 * NLRP7, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 7 *
NLRP12 NACHT, LRR and PYD domains-containing protein 12 is a protein that in humans is encoded by the ''NLRP12'' gene. NALPs are cytoplasmic proteins that form a subfamily within the larger CATERPILLER protein family. Most short NALPs, such as NALP12, ...
, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 12 Some NLRP genes encode a series of
NOD-like receptor The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs) (also known as nucleotide-binding leucine-rich repeat receptors), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the ...
family pyrin domains, including: *
NLRP5 NLRP5, short for NOD-like receptor family pyrin domain containing 5, is an intracellular protein that plays a role in early embryogenesis. NLRP5 is also known as NACHT, LRR and PYD domains-containing protein 5 (NALP5), Mater protein homolog (M ...
, a human gene that encodes the NOD-like receptor family pyrin domain containing 5 *
NLRP6 NLRP6, short for NOD-like receptor family pyrin domain containing 6, is an intracellular protein that plays a role in the immune system. It is also known as NALP6, PYPAF5, PAN3, and CLR11.4, and is one of 14 pyrin domain containing members of the ...
, a human gene that encodes the NOD-like receptor family pyrin domain containing 6 * NLRP8, a human gene that encodes the NOD-like receptor family pyrin domain containing 8 * NLRP9, a human gene that encodes the NOD-like receptor family pyrin domain containing 9 *
NLRP10 NLRP10, short for NOD-like receptor family pyrin domain containing 10, is an intracellular protein of mammals that functions in apoptosis and the immune system. It is also known as NALP10, NOD8, PAN5, Pynod, and CLR11.1, and is one of 14 pyrin d ...
, a human gene that encodes the NOD-like receptor family pyrin domain containing 10 * NLRP11, a human gene that encodes the NOD-like receptor family pyrin domain containing 11 * NLRP13, a human gene that encodes the NOD-like receptor family pyrin domain containing 13 * NLRP14, a human gene that encodes the NOD-like receptor family pyrin domain containing 14


References

{{reflist Intracellular receptors NOD-like receptors