NALP3
NACHT, LRR and PYD domains-containing protein 3 (NALP3) or cryopyrin is a protein that in humans is encoded by the NLRP3 (NOD-like receptor family, pyrin domain containing 3) gene.[1][2] The gene is also called cold induced autoinflammatory syndrome 1 (CIAS1) and is located on the long arm of chromosome 1. Another name for the protein is caterpiller-like receptor 1.1 (CLR1.1).
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. This protein may function as an activator of NF-κB signaling.
Mechanism
Crystalline structures activate the NLRP3 inflammasome in macrophages, leading to the production of IL-1β. Macrophage cell membrane binding to immobilized crystals induces IL-1β release, and this activation of the NLRP3 inflammasome is inhibited by blocking potassium efflux.[3]
Pathology
The encoded protein may play a role in the regulation of inflammation and apoptosis. Mutations in this gene 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, and neonatal-onset multisystem inflammatory disease (NOMID). Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene.[2]
Cryopyrin is contained in the intracellular inflammasome. It has also been linked to the pathogenesis of pseudogout, gout, and familial Mediterranean fever.
The NLRP3 inflammasome has a role in the neuroinflammation occurring in Alzheimer's disease.[4]
Deregulation of NLRP3 has been connected with cancer pathogenesis. For example, one study showed that all of the NLRP3 components are downregulated or completely lost in human hepatocellular carcinoma.[5] Besides, there are evidences that NLRP3 is regulated by ROS, though the precise mechanisms of such regulation is largely elusive.[6]
References
- ↑ Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD (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.
- ↑ 2.0 2.1 "Entrez Gene: NLRP3 NLR family, pyrin domain containing 3".
- ↑ Hari A, Zhang Y, Tu Z, Detampel P, Stenner M, Ganguly A et al. (2014). "Activation of NLRP3 inflammasome by crystalline structures via cell surface contact". Scientific Reports 4. doi:10.1038/srep07281. PMID 25445147.
- ↑ Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker 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. doi:10.1038/nature11729. PMC 3812809. PMID 23254930.
- ↑ Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X et al. (Jan 2014). "Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression". Laboratory Investigation; A Journal of Technical Methods and Pathology 94 (1): 52–62. doi:10.1038/labinvest.2013.126. PMID 24166187.
- ↑ Haneklaus M, O'Neill LA, Coll RC (Feb 2013). "Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments". Current Opinion in Immunology 25 (1): 40–45. doi:10.1016/j.coi.2012.12.004. PMID 23305783.
Further reading
- Tschopp J, Martinon F, Burns K (Feb 2003). "NALPs: a novel protein family involved in inflammation". Nature Reviews. Molecular Cell Biology 4 (2): 95–104. doi:10.1038/nrm1019. PMID 12563287.
- Martinon F, Tschopp J (Aug 2005). "NLRs join TLRs as innate sensors of pathogens". Trends in Immunology 26 (8): 447–54. doi:10.1016/j.it.2005.06.004. PMID 15967716.
- Mao M, Fu G, Wu JS, Zhang QH, Zhou J, Kan LX et al. (Jul 1998). "Identification of genes expressed in human CD34(+) hematopoietic stem/progenitor cells by expressed sequence tags and efficient full-length cDNA cloning". Proceedings of the National Academy of Sciences of the United States of America 95 (14): 8175–80. doi:10.1073/pnas.95.14.8175. PMC 20949. PMID 9653160.
- Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ et al. (Oct 2000). "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells". Genome Research 10 (10): 1546–60. doi:10.1101/gr.140200. PMC 310934. PMID 11042152.
- Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD (Nov 2001). "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome". Nature Genetics 29 (3): 301–5. doi:10.1038/ng756. PMID 11687797.
- Manji GA, Wang L, Geddes BJ, Brown M, Merriam S, Al-Garawi A et al. (Mar 2002). "PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kappa B". The Journal of Biological Chemistry 277 (13): 11570–5. doi:10.1074/jbc.M112208200. PMID 11786556.
- Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES (Jun 2002). "The PYRIN-CARD protein ASC is an activating adaptor for caspase-1". The Journal of Biological Chemistry 277 (24): 21119–22. doi:10.1074/jbc.C200179200. PMID 11967258.
- Dodé C, Le Dû N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G et al. (Jun 2002). "New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes". American Journal of Human Genetics 70 (6): 1498–506. doi:10.1086/340786. PMC 379138. PMID 11992256.
- Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E et al. (Jul 2002). "Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes". American Journal of Human Genetics 71 (1): 198–203. doi:10.1086/341357. PMC 384980. PMID 12032915.
- Fiorentino L, Stehlik C, Oliveira V, Ariza ME, Godzik A, Reed JC (Sep 2002). "A novel PAAD-containing protein that modulates NF-kappa B induction by cytokines tumor necrosis factor-alpha and interleukin-1beta". The Journal of Biological Chemistry 277 (38): 35333–40. doi:10.1074/jbc.M200446200. PMID 12093792.
- Aganna E, Martinon F, Hawkins PN, Ross JB, Swan DC, Booth DR et al. (Sep 2002). "Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis". Arthritis and Rheumatism 46 (9): 2445–52. doi:10.1002/art.10509. PMID 12355493.
- Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR et al. (Dec 2002). "De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases". Arthritis and Rheumatism 46 (12): 3340–8. doi:10.1002/art.10688. PMID 12483741.
- Hoffman HM, Gregory SG, Mueller JL, Tresierras M, Broide DH, Wanderer AA et al. (Feb 2003). "Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P". Human Genetics 112 (2): 209–16. doi:10.1007/s00439-002-0860-x. PMID 12522564.
- Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Núñez G (Mar 2003). "Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product". Biochemical and Biophysical Research Communications 302 (3): 575–80. doi:10.1016/S0006-291X(03)00221-3. PMID 12615073.
- Granel B, Philip N, Serratrice J, Ene N, Grateau G, Dodé C et al. (2003). "CIAS1 mutation in a patient with overlap between Muckle-Wells and chronic infantile neurological cutaneous and articular syndromes". Dermatology 206 (3): 257–9. doi:10.1159/000068883. PMID 12673085.
- Neven B, Callebaut I, Prieur AM, Feldmann J, Bodemer C, Lepore L et al. (Apr 2004). "Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU". Blood 103 (7): 2809–15. doi:10.1182/blood-2003-07-2531. PMID 14630794.
- O'Connor W, Harton JA, Zhu X, Linhoff MW, Ting JP (Dec 2003). "Cutting edge: CIAS1/cryopyrin/PYPAF1/NALP3/CATERPILLER 1.1 is an inducible inflammatory mediator with NF-kappa B suppressive properties". Journal of Immunology 171 (12): 6329–33. doi:10.4049/jimmunol.171.12.6329. PMID 14662828.
- McHale L, Tan X, Koehl P, Michelmore RW. "Plant NBS-LRR proteins: adaptable guards". Genome Biology 7 (4). doi:10.1186/gb-2006-7-4-212. PMC 1557992. PMID 16677430.
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