NLRP

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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. [1] NOD-like receptors are a type of pattern recognition receptor that are found in the cytosol of the cell, recognizing signals of antigens in the cell. [2] NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or pathogen-associated molecular patterns, such as such as peptidoglycan, which is found on some bacterial cells. [3] It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the inflammasome, including K + efflux and caspase 1 activation. [4] NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. [5] 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. [6]

Contents

Function

NLRP plays a key role in inflammation. It is a scaffolding protein 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. [7] NOD-like receptors, in general, activate caspase-1 and assist in the maturation of the proinflammatory cytokines IL-1β and IL-18. [2] However, not every NLRP forms an inflammasome and activates caspase-1; these NLRPs are referred to as non-canonical NLRPs. [6]

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. [8] 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. [9] 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. [10] 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. [11] [12]

Many NLRPs regulate the activation of NF-κB, which is a transcription factor that leads to the production of various pro-inflammatory cytokines, such as IL-1 and TNF-α. [2] [13] 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. [2] [7]

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 in the early stages of cell division. [14]

Structure

NLRP protein structure has a N-terminal PYD domain followed by NACHT domain and several leucine-rich repeats (LRR). [7] These PYD domains can interact with other PYD domains to allow for interaction between NRLP and other proteins also containing a PYD domain. [5] [15] Pyrin domains recruit the scaffold protein that activates the inflammasome. [7]

Expression

NLRPs are expressed in various parts of the body. These receptors are expressed in white blood cells, aiding the inflammation process upon activation by pathogen-associated molecular patterns, toxins, etc. [16] NLRPs are also expressed in many other locations in humans. For example, NLRP1 was found in the neurons of the brain, including pyramidal cells. NLRP1 is also expressed in the oligodendrocytes, which are cells in the central nervous system that myelinate neurons. [17] [18] NLRP1 has many alleles across the population, making it a very polymorphic gene. [7] NLRP6 is highly expressed in the intestine and is involved in fighting viral intestinal infections. [2]

A number of NLRPs, such as NLRP10, NLRP3, and NLRP1, are expressed in the keratinocytes, 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. [7]

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. [19] [20]

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. [5] NLRP3 has also been implicated in the development of diseases such as cancer, inflammatory bowel disease, and gout. [6]

Both NLRP1 and NLRP3 are involved in neurodegeneration. Amyloid beta aggregation and oligomerization, which is found in individuals with Alzheimer's disease, 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. [21]

Role in plants

Plants also recognize danger signals, and it is thought that plants utilize receptors similar to NLRPs to detect these signals. [5] 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. [22]

Genes

Some NLRP genes code for a series of NACHT, LRR and PYD domains-containing proteins, including:

Some NLRP genes encode a series of NOD-like receptor family pyrin domains, including:

Related Research Articles

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

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 the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

<span class="mw-page-title-main">CARD (domain)</span> Interaction motifs found in a wide array of proteins

Caspase recruitment domains, or caspase activation and recruitment domains (CARDs), 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 interactions between individual CARDs. CARDs are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.

<span class="mw-page-title-main">Caspase 1</span> Protein-coding gene in the species Homo sapiens

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 pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

<span class="mw-page-title-main">NLRP3</span> Human protein and coding gene

NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">PYCARD</span> Human protein and coding gene

PYCARD, often referred to as ASC, is a protein that in humans is encoded by the PYCARD gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen infection, however, it relocalizes rapidly to the cytoplasm, perinuclear space, endoplasmic reticulum and mitochondria and it is a key adaptor protein in activation of the inflammasome.

<span class="mw-page-title-main">NLRP1</span> Human protein-coding gene

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. NLRP1 is expressed by a variety of cell types, which are predominantly epithelial or hematopoietic. The expression is also seen within glandular epithelial structures including the lining of the small intestine, stomach, airway epithelia and in hairless or glabrous skin. NLRP1 polymorphisms are associated with skin extra-intestinal manifestations in CD. Its highest expression was detected in human skin, in psoriasis and in vitiligo. Polymorphisms of NLRP1 were found in lupus erythematosus and diabetes type 1. Variants of mouse NLRP1 were found to be activated upon N-terminal cleavage by the protease in anthrax lethal factor.

<span class="mw-page-title-main">NLRC4</span> Protein-coding gene in the species Homo sapiens

NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the NLRC4 gene.

<span class="mw-page-title-main">NLRP2</span> Protein-coding gene in the species Homo sapiens

NACHT, LRR and PYD domains-containing protein 2 is a protein that in humans is encoded by the NLRP2 gene.

<span class="mw-page-title-main">NLRP7</span> Protein-coding gene in the species Homo sapiens

NACHT, LRR and PYD domains-containing protein 7 is a protein that in humans is encoded by the NLRP7 gene.

<span class="mw-page-title-main">NLRP12</span> Protein-coding gene in the species Homo sapiens

NACHT, LRR and PYD domains-containing protein 12 is a protein that in humans is encoded by the NLRP12 gene.

<span class="mw-page-title-main">NLRP4</span> Protein-coding gene in the species Homo sapiens

NACHT, LRR and PYD domains-containing protein 4 is a protein that in humans is encoded by the NLRP4 gene.

<span class="mw-page-title-main">AIM2</span> Protein-coding gene in the species Homo sapiens

Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the AIM2 gene.

<span class="mw-page-title-main">NOD-like receptor</span> Class of proteins

The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the cell via phagocytosis or pores, and damage-associated molecular patterns (DAMPs) that are associated with cell stress. They are types of pattern recognition receptors (PRRs), and play key roles in the regulation of innate immune response. NLRs can cooperate with toll-like receptors (TLRs) and regulate inflammatory and apoptotic response.

<span class="mw-page-title-main">Inflammasome</span> Cytosolic multiprotein complex that mediates the activation of Caspase 1

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-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of gasdermin D. The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane. Additionally, inflammasomes can be incorporated into larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

<span class="mw-page-title-main">Death domain</span>

The death domain (DD) is a protein interaction module composed of a bundle of six alpha-helices. DD is a subclass of protein motif known as the death fold and is related in sequence and structure to the death effector domain (DED) and the caspase recruitment domain (CARD), which work in similar pathways and show similar interaction properties. DD bind each other forming oligomers. Mammals have numerous and diverse DD-containing proteins. Within these proteins, the DD domains can be found in combination with other domains, including: CARDs, DEDs, ankyrin repeats, caspase-like folds, kinase domains, leucine zippers, leucine-rich repeats (LRR), TIR domains, and ZU5 domains.

<span class="mw-page-title-main">Pyrin domain</span>

A pyrin domain is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the pyrin protein, or marenostrin, encoded by MEFV. The mutation of the MEFV gene is the cause of the disease known as Familial Mediterranean Fever. The domain is encoded in 23 human proteins and at least 31 mouse genes.

<span class="mw-page-title-main">NLRP11</span> Protein-coding gene in the species Homo sapiens

NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of caterpiller. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. They are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.

References

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  3. ↑ Girardin, Stephen E.; Philpott, Dana J. (July 2004). "Mini-review: The role of peptidoglycan recognition in innate immunity". European Journal of Immunology. 34 (7): 1777–1782. doi: 10.1002/eji.200425095 . ISSN   0014-2980. PMID   15214025. S2CID   29894269.
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  14. ↑ Amoushahi, Mahboobeh; Sunde, Lone; Lykke-Hartmann, Karin (2019-08-01). "The pivotal roles of the NOD-like receptors with a PYD domain, NLRPs, in oocytes and early embryo development†". Biology of Reproduction. 101 (2): 284–296. doi: 10.1093/biolre/ioz098 . ISSN   0006-3363. PMID   31201414.
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