NOD-like receptor

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Structure and domain organization of NOD2, a human NOD-like receptor Nod-like receptor 2.png
Structure and domain organization of NOD2, a human NOD-like receptor

The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs) (also known as nucleotide-binding leucine-rich repeat receptors), [1] 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), [2] 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.

Contents

NLRs primarily recognize Gram-positive bacteria, whereas TLRs primarily recognize Gram-negative bacteria. They are found in lymphocytes, macrophages, dendritic cells and also in non-immune cells, for example in epithelium. [3] NLRs are highly conserved through evolution. Their homologs have been discovered in many different animal species (APAF1) [4] [5] and also in the plant kingdom (disease-resistance R protein). [5]

Structure

NLRs contain 3 domains – central NACHT (NOD or NBD – nucleotide-binding domain) domain, which is common to all NLRs, most of NLRs have also C-terminal leucine-rich repeat (LRR) and variable N-terminal interaction domain. NACHT domain mediates ATP-dependent self-oligomerization and LRR senses the presence of ligand. N-terminal domain is responsible for homotypic protein-protein interaction and it can consist of caspase recruitment domain (CARD), pyrin domain (PYD), acidic transactivating domain or baculovirus inhibitor repeats (BIRs). [3] [6]

Nomenclature and system

Names as CATERPILLER, NOD, NALP, PAN, NACHT, PYPAF were used to describe the NLRs family. The nomenclature was unified by the HUGO Gene Nomenclature Committee in 2008. The family was characterized as NLRs to provide description of the families features – NLR means nucleotide-binding domain and leucine-rich repeat containing gene family. [7]

This system divides NLRs into 4 subfamilies based on the type of N-terminal domain:

There is also an additional subfamily NLRX which doesn't have significant homology to any N-terminal domain. A member of this subfamily is NLRX1. [8]

On the other hand, NLRs can be divided into 3 subfamilies with regard to their phylogenetic relationships:

Subfamily NODs

NODs subfamily consists of NOD1, NOD2, NOD3, NOD4 with CARD domain, CIITA containing acidic transactivator domain and NOD5 without any N-terminal domain. [9] [10]

Signalling

The well-described receptors are NOD1 and NOD2. The recognition of their ligands recruits oligomerization of NACHT domain and CARD-CARD interaction with CARD-containing serine-threonin kinase RIP2 which leads to activation of RIP2. [11] RIP2 mediates the recruitment of kinase TAK1 which phosphorylates and activates IκB kinase. The activation of IκB kinase results in the phosphorylation of inhibitor IκB which releases NF-κB and its nuclear translocation. NF-κB then activates expression of inflammatory cytokines. [12] Mutations in NOD2 are associated with Crohn's disease [13] or Blau syndrome. [14]

Ligands

NOD1 and NOD2 recognize peptidoglycan motifs from bacterial cell which consists of N-acetylglucosamine and N-acetylmuramic acid. These sugar chains are cross-linked by peptide chains that can be sensed by NODs. NOD1 recognizes a molecule called meso-diaminopimelic acid (meso-DAP) mostly found in Gram-negative bacteria (for example Helicobacter pylori , Pseudomonas aeruginosa ). NOD2 proteins can sense intracellular muramyl dipeptide (MDP), typical for bacteria such as Streptococcus pneumoniae or Mycobacterium tuberculosis . [3] [10]

Subfamilies NLRPs and IPAF

NLRPs subfamily contains NLRP1-NLRP14 that are characterized by the presence of PYD domain. IPAF subfamily has two members – IPAF with CARD domain and NAIP with BIR domain. [9] [10]

Signalization

NLRPs and IPAF subfamilies are involved in the formation of the inflammasome. The best characterized inflammasome is NLRP3, the activation through PAMPs or DAMPs leads to the oligomerization. [9] The pyrin domain of NLRs binds to an adaptor protein ASC (PYCARD) via PYD-PYD interaction. ASC contains PYD and CARD domain and links the NLRs to inactive form of caspase 1 through the CARD domain. [15] All these protein-protein interaction form a complex called the inflammasome. The aggregation of the pro-caspase-1 causes the autocleavage and formation of an active enzyme. Caspase-1 is important for the proteolytic processing of the pro-inflammatory cytokines IL-1β and IL-18. [9] [10] NLRP3 mutations are responsible for the autoinflammatory disease familial cold autoinflammatory syndrome or Muckle–Wells syndrome. [16] [17]

Ligands

There are three well-characterized inflammasomes – NLRP1, NLRP3 and IPAF. The formation of NLRP3 inflammasome can be activated by PAMPs such as microbial toxins (for example alpha-toxin of Staphylococcus aureus ) or whole pathogens, for instance Candida albicans , Saccharomyces cerevisiae , Sendai virus, Influenza. NLRP3 recognize also DAMPs which indicate stress in the cell. The danger molecule can be extracellular ATP, extracellular glucose, monosodium urate (MSU) crystals, calcium pyrophosphate dihydrate (CPPD), alum, cholesterol or environmental irritants – silica, asbestos, UV irradiation and skin irritants. The presence of these molecules causes a production of ROS and K+ efflux. NLRP1 recognizes lethal toxin from Bacillus anthracis and muramyl dipeptide. IPAF senses flagellin from Salmonella typhimurium , Pseudomonas aeruginosa , Listeria monocytogenes . [3] [9] [10]

See also

Related Research Articles

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">NOD2</span> Protein-coding gene in humans

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also known as caspase recruitment domain-containing protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1), 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. It recognizes bacterial molecules (peptidoglycans) and stimulates an immune reaction.

<span class="mw-page-title-main">NOD1</span> Protein receptor that recognizes bacterial molecules and stimulates an immune reaction

Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a protein receptor that in humans is encoded by the NOD1 gene. It recognizes bacterial molecules and stimulates an immune reaction.

<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">RIPK2</span> Protein-coding gene in humans

Receptor-interacting serine/threonine-protein kinase 2 is an enzyme that in humans is encoded by the RIPK2 gene.

<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">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">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">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

NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. 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. 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. 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. 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.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

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

  1. ↑ Mahla, Ranjeet (2013). "Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology". Front Immunol. 4: 248. doi: 10.3389/fimmu.2013.00248 . PMC   3759294 . PMID   24032031.
  2. ↑ Mahla RS, Reddy MC, Prasad DV, Kumar H (September 2013). "Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology". Frontiers in Immunology. 4: 248. doi: 10.3389/fimmu.2013.00248 . PMC   3759294 . PMID   24032031.
  3. 1 2 3 4 Franchi L, Warner N, Viani K, Nuñez G (2009). "Function of Nod-like receptors in microbial recognition and host defense". Immunol Rev. 227 (1): 106–28. doi:10.1111/j.1600-065X.2008.00734.x. PMC   2679989 . PMID   19120480.
  4. ↑ Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G (2001). "Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB". J Biol Chem. 276 (7): 4812–8. doi: 10.1074/jbc.M008072200 . PMID   11087742.
  5. 1 2 Inohara N, Ogura Y, Chen FF, Muto A, Nuñez G (2001). "Human Nod1 confers responsiveness to bacterial lipopolysaccharides". J Biol Chem. 276 (4): 2551–4. doi: 10.1074/jbc.M009728200 . PMID   11058605.
  6. ↑ Shaw MH, Reimer T, Kim YG, Nuñez G (2008). "NOD-like receptors (NLRs): bona fide intracellular microbial sensors". Curr Opin Immunol. 20 (4): 377–82. doi:10.1016/j.coi.2008.06.001. PMC   2572576 . PMID   18585455.
  7. 1 2 Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, et al. (2008). "The NLR gene family: a standard nomenclature". Immunity. 28 (3): 285–7. doi:10.1016/j.immuni.2008.02.005. PMC   2630772 . PMID   18341998.
  8. ↑ Tattoli I, Carneiro LA, Jéhanno M, Magalhaes JG, Shu Y, Philpott DJ, et al. (2008). "NLRX1 is a mitochondrial NOD-like receptor that amplifies NF-kappaB and JNK pathways by inducing reactive oxygen species production". EMBO Rep. 9 (3): 293–300. doi:10.1038/sj.embor.7401161. PMC   2267388 . PMID   18219313.
  9. 1 2 3 4 5 6 Schroder K, Tschopp J (2010). "The inflammasomes". Cell. 140 (6): 821–32. doi: 10.1016/j.cell.2010.01.040 . PMID   20303873.
  10. 1 2 3 4 5 Chen G, Shaw MH, Kim YG, Nuñez G (2009). "NOD-like receptors: role in innate immunity and inflammatory disease". Annu Rev Pathol. 4: 365–98. doi:10.1146/annurev.pathol.4.110807.092239. PMID   18928408.
  11. ↑ Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M, Body-Malapel M, et al. (2007). "RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs". J Immunol. 178 (4): 2380–6. doi: 10.4049/jimmunol.178.4.2380 . PMID   17277144.
  12. ↑ Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Núñez G, et al. (2008). "A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation". EMBO J. 27 (2): 373–83. doi:10.1038/sj.emboj.7601962. PMC   2234345 . PMID   18079694.
  13. ↑ Cantó E, Ricart E, Busquets D, Monfort D, García-Planella E, González D, et al. (2007). "Influence of a nucleotide oligomerization domain 1 (NOD1) polymorphism and NOD2 mutant alleles on Crohn's disease phenotype". World J Gastroenterol. 13 (41): 5446–53. doi: 10.3748/wjg.v13.i41.5446 . PMC   4171278 . PMID   17907287.
  14. ↑ Okafuji I, Nishikomori R, Kanazawa N, Kambe N, Fujisawa A, Yamazaki S, et al. (2009). "Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis". Arthritis Rheum. 60 (1): 242–50. doi:10.1002/art.24134. hdl: 2433/124253 . PMID   19116920.
  15. ↑ Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES (2002). "The PYRIN-CARD protein ASC is an activating adaptor for caspase-1". J Biol Chem. 277 (24): 21119–22. doi: 10.1074/jbc.C200179200 . PMID   11967258.
  16. ↑ Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD (2001). "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome". Nat Genet. 29 (3): 301–5. doi:10.1038/ng756. PMC   4322000 . PMID   11687797.
  17. ↑ Kubota T, Koike R (2007). "[Biological and clinical aspects of Muckle-Wells syndrome]". Nihon Rinsho Meneki Gakkai Kaishi. 30 (2): 114–22. doi: 10.2177/jsci.30.114 . PMID   17473514.
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