NLRP3

Official Full Name

NLR family pyrin domain containing 3

Organism

Homo sapiens

Gene ID

114548

Background

This gene encodes a pyrin-like protein containing a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase recruitment domain, and is a member of the NLRP3 inflammasome complex. This complex functions as an upstream activator of NF-kappaB signaling, and it plays a role in the regulation of inflammation, the immune response, and apoptosis. The SARS-CoV 3a protein, a transmembrane pore-forming viroporin, has been shown to activate the NLRP3 inflammasome via the formation of ion channels in macrophages. Mutations in this gene are associated with familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), keratoendotheliitis fugax hereditarian, and deafness, autosomal dominant 34, with or without inflammation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Alternative 5' UTR structures are suggested by available data; however, insufficient evidence is available to determine if all of the represented 5' UTR splice patterns are biologically valid. [provided by RefSeq, Aug 2020]

Synonyms

AII; AVP; FCU; MWS; FCAS; KEFH; CIAS1; FCAS1; NALP3; C1orf7; CLR1.1; DFNA34; PYPAF1; AGTAVPRL

Cat.No.	Product Name	Price
CSC-DC010439	Panoply™ Human NLRP3 Knockdown Stable Cell Line	Inquiry
CSC-SC010439	Panoply™ Human NLRP3 Over-expressing Stable Cell Line	Inquiry
CSC-RO01320	Mouse Nlrp3 Stable Cell Line - MC3T3-E1	Inquiry
CSC-RO01372	Mouse Nlrp3 Stable Cell Line - RAW 264.7	Inquiry

Cat.No.	Product Name	Price
AD10840Z	Human NLRP3 adenoviral particles	Inquiry
LV19638L	human NLRP3 (NM_001127462) lentivirus particles	Inquiry
LV19639L	human NLRP3 (NM_004895) lentivirus particles	Inquiry
LV19640L	human NLRP3 (NM_183395) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH352968	shRNA set against Mouse NLRP3 (NM_145827.3)	Inquiry
SHG086779	shRNA set against Human NLRP3(NM_004895.4)	Inquiry
SHG086797	shRNA set against Mouse Nlrp3(NM_145827.3)	Inquiry
SHH352964	shRNA set against Human NLRP3 (NM_183395.2)	Inquiry

Cat.No.	Product Name	Price
CDCR032496	Human NLRP3 ORF clone (NM_001127461.2)	Inquiry
CDCR325010	Human NLRP3 ORF Clone(NM_183395.2)	Inquiry
MiUTR1H-06801	NLRP3 miRNA 3'UTR clone	Inquiry
MiUTR1M-07688	NLRP3 miRNA 3'UTR clone	Inquiry
MiUTR1R-00999	NLRP3 miRNA 3'UTR clone	Inquiry
MiUTR3H-08429	NLRP3 miRNA 3'UTR clone	Inquiry
MiUTR3H-08430	NLRP3 miRNA 3'UTR clone	Inquiry
MiUTR3H-08431	NLRP3 miRNA 3'UTR clone	Inquiry
MiUTR3H-08433	NLRP3 miRNA 3'UTR clone	Inquiry
CDCB186896	Rabbit NLRP3 ORF clone (XM_002723157.2)	Inquiry
CDCH391965	Rat NLRP3 ORF clone(NM_001191642.1)	Inquiry
CDCL138709	Mouse Nlrp3 ORF clone (NM_145827.3)	Inquiry
CDCR348705	Human NLRP3 ORF Clone(NM_001127462.2)	Inquiry
CDCS407269	Human NLRP3 ORF Clone (BC117211)	Inquiry

Detailed Information

The NLRP3 inflammatory corpuscle is composed of NLRP3, apoptosis-associated speck-like protein containing a CARD domain (ASC), and pro-caspase-1. NLRP3 mainly consists of three parts, the leucine-rich-repeat domain (LRR), which recognizes microbes and endogenous risk signals; the characteristic nucleotide oligomerization domain of the middle segment Nucleoside triphosphatase domain (NACTH), which acts to mediate NLR oligomerization and form the core structure of inflammatory bodies; the N-terminal effector domain, mainly including pyrin domain (PYD), caspase recruitment domain (Caspase recruitment domain, CARD) and baculovirus inhibitor of apoptosis repeat domain (BIR), etc., are involved in the signal transduction process. ASC is an important class of adaptor proteins in the cell. It consists of PYD and CARD. It can interact with PYD of NIR and recruit pro-caspase-1 through CARD domain to mediate NLRP3 activation of caspase-1.

NLRP3 Figure 1. NLRP3 inflammasome priming and activation. (Karen V. Swanson, et al. 2019)

NLRP3 Inflammatory Bodies and Related Diseases

The NLRP3 inflammatory corpuscle function-acquired mutation was originally found to be closely associated with cryopyrin-associated periodic syndromes (CAPS), a rare autosomal dominant autoinflammatory response. Three consecutive progressive inflammatory dysfunctions constitute a continuous clinical process, namely familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), and chronic infantile cutaneous neurological articular syndrome (CINCA). The mutation mainly occurs in the NACTH domain, causing the NLRP3 structure to change and making it unable to self-inhibit at rest and is always active. This result will result in sustained NF-κB, caspase-1 pathway activation, which ultimately leads to the spontaneous secretion of IL-1β and IL-18, causing the corresponding clinical symptoms in CAPS patients.

After the blood flow is restored on the basis of ischemia, the tissue damage is aggravated, and even irreversible damage occurs. This is called ischaemia-reperfusion injury (I/R). The mechanism of I/R has not yet been fully elucidated. It is currently believed that the role of free radicals, intracellular calcium overload and activation of white blood cells are important pathogenesis of I/R. NLRP3 inflammatory bodies are also involved in mediating myocardial ischemia-reperfusion injury. After myocardial ischemia and reperfusion, the expression of NLRP3 was significantly up-regulated in cardiomyocytes, especially fibroblasts, and the levels of IL-1β and IL-18 were significantly increased. However, the infarct size of NLRP3-deficient mice was significantly reduced and the cardiac contractile function was enhanced. Damaged cardiomyocytes release ATP, activate NLRP3 inflammatory corpuscle formation, promote IL-1β and IL-18 release, and cause inflammatory damage. The inflammatory response further stimulates the release of other chemokines and cytokines, induces inflammatory cell infiltration of ischemic myocardium, which in turn aggravates myocardial damage. In addition, inflammatory cell death caused by inflammatory body activation is also involved in the process of myocardial injury.

The inflammatory response is one of the important pathogenesis of atherosclerosis (AS). Cholesterol crystals activate NLRP3 inflammatory bodies, leading to the maturation and secretion of IL-1β, which plays an important role in the initiation of AS. Bone marrow transplantation was performed after fatal irradiation in AS-susceptible mice knocked out by low-density lipoprotein receptor (LDLR) gene. The bone marrow of NLRP3, ASC and IL-1α/β knockout mice were transplanted respectively, and the cholesterol-rich diet was administered. The area of aortic atherosclerotic lesions in the bone marrow transplantation group was observed to be 69% lower than that of the control group, and transplantation was performed. Serum IL-18 levels were significantly lower in the group than in the control group. In addition, NLRP3 inflammatory bodies are highly expressed in AS plaques, and their activation is regulated by ox-LDL in macrophages, suggesting that NLRP3 inflammatory bodies may be involved in mediating AS inflammatory processes.

References:

Mangan, M. S. J. , Olhava, E. J. , Roush, W. R. , Martin, S. H. , Glick, G. D. , & Eicke, L. . (2018). Targeting the nlrp3 inflammasome in inflammatory diseases. Nature Reviews Drug Discovery.
Karen V. Swanson, Meng Deng & Jenny P.-Y. Ting. (2019). The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology.
Sarah, D. , Ema, O. , & Matthew, C. . (2015). Targeting the nlrp3 inflammasome in chronic inflammatory diseases: current perspectives. Journal of Inflammation Research, 15-.

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