NLRP3

Last updated
NLRP3
NLRP3 protein.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NLRP3 , AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1, FCAS, FCAS1, FCU, MWS, NALP3, PYPAF1, NLR family, pyrin domain containing 3, NLR family pyrin domain containing 3, DFNA34, KEFH
External IDs OMIM: 606416; MGI: 2653833; HomoloGene: 3600; GeneCards: NLRP3; OMA:NLRP3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_145827
NM_001359638

RefSeq (protein)

NP_665826
NP_001346567

Location (UCSC) Chr 1: 247.42 – 247.45 Mb Chr 11: 59.43 – 59.46 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR, and PYD domains-containing protein 3 [NALP3] and cryopyrin), is a protein that in humans is encoded by the NLRP3 gene [5] located on the long arm of chromosome 1. [6]

Contents

NLRP3 is expressed predominantly in macrophages and as a component of the inflammasome, [7] [8] :436 detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NLRP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of organ specific autoimmune diseases.

Nomenclature

NACHT, LRR, and PYD are respectively acronyms for:

The NACHT, LRR and PYD domains-containing protein 3 is also called:

Structure

This gene encodes a pyrin-like protein which contains a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with pyrin domain (PYD) of apoptosis-associated speck-like protein containing a CARD (ASC). Proteins which contain the caspase recruitment domain, CARD, have been shown to be involved in inflammation and immune response. [5]

Function

NLRP3 is a component of the innate immune system that functions as a pattern recognition receptor (PRR) that recognizes pathogen-associated molecular patterns (PAMPs). [14] NLRP3 belongs to the NOD-like receptor (NLR) subfamily of PRRs and NLRP3 together with the adaptor ASC protein PYCARD forms a caspase-1 activating complex known as the NLRP3 inflammasome. NLRP3 in the absence of activating signal is kept in an inactive state complexed with HSP90 and SGT1 in the cytoplasm. NLRP3 inflammasome detects danger signals such as crystalline uric acid and extracellular ATP released by damaged cells. These signals release HSP90 and SGT1 from and recruit ASC protein and caspase-1 to the inflammasome complex. Caspase-1 within the activated NLRP3 inflammasome complex in turn activates the inflammatory cytokine, IL-1β. [14]

The NLRP3 inflammasome appears to be activated by changes in intracellular potassium [15] caused by potassium efflux from mechanosensitive ion channels located in the cell membrane. [16] It appears that NLRP3 is also regulated by reactive oxygen species (ROS), though the precise mechanisms of such regulation has not been determined. [17]

It is suggested that NLRP3 provides protection against Streptococcus pneumoniae infections by activating STAT6 and SPDEF. [18]

Pathology

Mutations in the NLRP3 gene result in autoactive inflammasomes [19] and have been associated with a spectrum of dominantly inherited autoinflammatory diseases called cryopyrin-associated periodic syndrome (CAPS). This includes familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal onset multisystem inflammatory disease (NOMID), and keratoendotheliitis fugax hereditaria. [5] [20]

Defects in this gene have also been linked to familial Mediterranean fever. [21] In addition, the NLRP3 inflammasome has a role in the pathogenesis of gout, [14] hemorrhagic stroke [22] and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer's, Parkinson's, and prion diseases. [23] [24] [25] Amelioration of mouse models of many diseases has been shown to occur by deletion of the NLRP3 inflammasome, including gout, type 2 diabetes, multiple sclerosis, Alzheimer's disease, and atherosclerosis. [26] The compound β-hydroxybutyrate has been shown to block NLRP3 activation, and thus may be of benefit for many of these diseases. [27]

Deregulation of NLRP3 has been connected with carcinogenesis. For example, all the components of the NLRP3 inflammasome are downregulated or completely lost in human hepatocellular carcinoma. [28]

Inhibition

The NLRP3 inflammasome has garnered attention as a potential drug target for a variety of diseases underpinned by inflammation. The diarylsulfonylurea MCC-950 has been identified as a potent and selective NLRP3 inhibitor [29] able to lock the inactive NLRP3 structure. [30] Nodthera and Inflazome, have entered phase I clinical trials with NLRP3 inhibitors. Another NLRP3 antagonist is Dapansutrile (OLT1177). This β-sulfonyl nitrile molecule compound was developed by Olactec Therapeutics, and is a selective NLRP3 inhibitor. Dapansutrile, been used in clinical trials as a remedy for heart failure, osteoarthritis and gouty arthritis. [31]

References and notes

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162711 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032691 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 Anon. (2015). "Entrez Gene: NLRP3 NLR family, pyrin domain containing 3 [Homo sapiens (human)], Gene ID: 114548 (updated on 13-Nov-2015)". Bethesda, MD, USA: National Center for Biotechnology Information, National Library of Medicine. Retrieved 13 November 2015.
  6. Hoffman HM, Wright FA, Broide DH, et al. (May 2000). "Identification of a locus on chromosome 1q44 for familial cold urticaria". American Journal of Human Genetics. 66 (5): 1693–8. doi:10.1086/302874. PMC   1378006 . PMID   10741953.
  7. Tao JH, Zhang Y, Li XP (Dec 2013). "P2X7R: a potential key regulator of acute gouty arthritis". review. Seminars in Arthritis and Rheumatism. 43 (3): 376–80. doi:10.1016/j.semarthrit.2013.04.007. PMID   23786870.
  8. Lu A, Wu H (Feb 2015). "Structural mechanisms of inflammasome assembly". review. The FEBS Journal. 282 (3): 435–44. doi:10.1111/febs.13133. PMC   6400279 . PMID   25354325.
  9. Koonin EV, Aravind L (May 2000). "The NACHT family - a new group of predicted NTPases implicated in apoptosis and MHC transcription activation". Trends in Biochemical Sciences. 25 (5): 223–4. doi:10.1016/S0968-0004(00)01577-2. PMID   10782090.
  10. Pueyo I, Jiménez JR, Hernández J, et al. (Sep 1978). "Carcinoid syndrome treated by hepatic embolization". AJR. American Journal of Roentgenology. 131 (3): 511–3. doi: 10.2214/ajr.131.3.511 . PMID   99001.
  11. 1 2 Jha S, Ting JP (Dec 2009). "Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases". Journal of Immunology. 183 (12): 7623–9. doi:10.4049/jimmunol.0902425. PMC   3666034 . PMID   20007570.
  12. Bertin J, DiStefano PS (Dec 2000). "The PYRIN domain: a novel motif found in apoptosis and inflammation proteins". review. Cell Death and Differentiation. 7 (12): 1273–4. doi: 10.1038/sj.cdd.4400774 . PMID   11270363.
  13. Q96P20
  14. 1 2 3 Martinon F (Mar 2008). "Detection of immune danger signals by NALP3". review. Journal of Leukocyte Biology. 83 (3): 507–11. doi: 10.1189/jlb.0607362 . PMID   17982111.
  15. Tapia-Abellán A, Angosto-Bazarra D, Alarcón-Vila C, et al. (2021-09-17). "Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation". Science Advances. 7 (38): eabf4468. Bibcode:2021SciA....7.4468T. doi:10.1126/sciadv.abf4468. ISSN   2375-2548. PMC   8443177 . PMID   34524838.
  16. Hari A, Zhang Y, Tu Z, et al. (2014). "Activation of NLRP3 inflammasome by crystalline structures via cell surface contact". Scientific Reports. 4: 7281. Bibcode:2014NatSR...4E7281H. doi:10.1038/srep07281. PMC   4250918 . PMID   25445147.
  17. Haneklaus M, O'Neill LA, Coll RC (Feb 2013). "Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments". review. Current Opinion in Immunology. 25 (1): 40–45. doi:10.1016/j.coi.2012.12.004. hdl: 2262/72554 . PMID   23305783.
  18. Fang R, Uchiyama R, Sakai S, et al. (September 2019). "ASC and NLRP3 maintain innate immune homeostasis in the airway through an inflammasome-independent mechanism". Mucosal Immunology. 12 (5): 1092–1103. doi: 10.1038/s41385-019-0181-1 . PMID   31278375.
  19. Molina-López C, Hurtado-Navarro L, García CJ, et al. (2024-02-06). "Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production". Nature Communications. 15 (1): 1096. Bibcode:2024NatCo..15.1096M. doi:10.1038/s41467-024-44990-0. ISSN   2041-1723. PMC   10847128 . PMID   38321014.
  20. Turunen JA, Wedenoja J, Repo P, et al. (Jan 2018). "Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene". American Journal of Ophthalmology. 184: 41–50. doi: 10.1016/j.ajo.2018.01.017 . PMID   29366613.
  21. Church LD, Cook GP, McDermott MF (Jan 2008). "Primer: inflammasomes and interleukin 1beta in inflammatory disorders". review. Nature Clinical Practice Rheumatology. 4 (1): 34–42. doi:10.1038/ncprheum0681. PMID   18172447. S2CID   19986204.
  22. Ren H, Han R, Chen X, et al. (May 2020). "Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update". J Cereb Blood Flow Metab. 40 (9): 1752–1768. doi:10.1177/0271678X20923551. PMC   7446569 . PMID   32423330.
  23. Liu-Bryan R (Jan 2010). "Intracellular innate immunity in gouty arthritis: role of NALP3 inflammasome". review. Immunology and Cell Biology. 88 (1): 20–3. doi:10.1038/icb.2009.93. PMC   4337950 . PMID   19935768.
  24. Heneka MT, Kummer MP, Stutz A, et al. (Jan 2013). "NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice". Nature. 493 (7434): 674–8. Bibcode:2013Natur.493..674H. doi:10.1038/nature11729. PMC   3812809 . PMID   23254930.
  25. Shi F, Kouadir M, Yang Y (Aug 2015). "NALP3 inflammasome activation in protein misfolding diseases". review. Life Sciences. 135: 9–14. doi:10.1016/j.lfs.2015.05.011. PMID   26037399.
  26. Levy M, Thaiss CA, Elinav E (2015). "Taming the inflammasome" (PDF). Nature Medicine . 21 (3): 213–215. doi:10.1038/nm.3808. PMID   25742454. S2CID   6659540.
  27. Youm YH, Nguyen KY, Grant RW, et al. (2015). "The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease". Nature Medicine . 21 (3): 263–269. doi:10.1038/nm.3804. PMC   4352123 . PMID   25686106.
  28. Wei Q, Mu K, Li T, et al. (Jan 2014). "Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression". Laboratory Investigation. 94 (1): 52–62. doi: 10.1038/labinvest.2013.126 . PMID   24166187.
  29. Coll RC, Robertson AA, Chae JJ, et al. (March 2015). "A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases". Nature Medicine. 21 (3): 248–55. doi:10.1038/nm.3806. PMC   4392179 . PMID   25686105.
  30. Tapia-Abellán A, Angosto-Bazarra D, Martínez-Banaclocha H, et al. (June 2019). "MCC950 closes the active conformation of NLRP3 to an inactive state". Nature Chemical Biology. 15 (6): 560–564. doi:10.1038/s41589-019-0278-6. ISSN   1552-4450. PMC   7116292 . PMID   31086329.
  31. Alzheimer's Drug Discovery Foundation D. "Dapansutrile" (PDF).

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">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

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. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

<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.

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">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

Nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain (PYD)-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.

Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of 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

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.

<span class="mw-page-title-main">Dapansutrile</span> Chemical compound

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 inflammasome.

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