NALP3

NLR family, pyrin domain containing 3
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3QF2
Identifiers
Symbols	NLRP3 ; AGTAVPRL; AII; AVP; C1orf7; CIAS1; CLR1.1; FCAS; FCAS1; FCU; MWS; NALP3; PYPAF1
External IDs	OMIM: 606416 MGI: 2653833 HomoloGene: 3600 ChEMBL: 1741208 GeneCards: NLRP3 Gene
Gene ontology Molecular function • protein binding • ATP binding • peptidoglycan binding Cellular component • cytoplasm • cytosol • NLRP3 inflammasome complex Biological process • negative regulation of acute inflammatory response • apoptotic process • activation of cysteine-type endopeptidase activity involved in apoptotic process • defense response • inflammatory response • signal transduction • detection of biotic stimulus • negative regulation of NF-kappaB transcription factor activity • interleukin-1 beta production • interleukin-18 production • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway • negative regulation of NF-kappaB import into nucleus • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process • NLRP3 inflammasome complex assembly • innate immune response • interleukin-1 secretion • negative regulation of interleukin-1 beta secretion • positive regulation of interleukin-1 beta secretion • negative regulation of inflammatory response • positive regulation of NF-kappaB transcription factor activity • protein oligomerization • defense response to virus • cellular response to lipopolysaccharide Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE NLRP3 216015 s at tn.png
File:PBB GE NLRP3 207075 at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	114548	216799
Ensembl	ENSG00000162711	ENSMUSG00000032691
UniProt	Q96P20	Q8R4B8
RefSeq (mRNA)	NM_001079821	NM_145827
RefSeq (protein)	NP_001073289	NP_665826
Location (UCSC)	Chr 1: 247.42 – 247.45 Mb	Chr 11: 59.54 – 59.57 Mb
PubMed search	[1]	[2]

NACHT, LRR and PYD domains-containing protein 3 (NALP3) also known by cryopyrin is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

NALP3 is expressed predominantly in macrophages and as a component of the inflammasome, detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NALP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated a number of organ specific autoimmune diseases.

Nomenclature

NACHT, LRR, and PYD are respectively acronyms for:

• NACHT – NAIP (neuronal apoptosis inhibitor protein), C2TA [class 2 transcription activator, of the MHC, HET-E (heterokaryon incompatibility) and TP1 (telomerase-associated protein 1)
• LRR – "leucine-rich repeat" and is synonymous with NLR, for or nucleotide-binding domain, leucine-rich repeat"
• PYD – "PYRIN domain," after the pyrin proteins The NLRP3 gene name abbreviates "NLR family, pyrin domain containing 3," where NLR refers to "nucleotide-binding domain, leucine-rich repeat."

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

• cold induced autoinflammatory syndrome 1 (CIAS1),
• caterpiller-like receptor 1.1 (CLR1.1), and
• PYRIN-containing APAF1-like protein 1 (PYPAF1).

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.

Function

NALP3 is a component of the innate immune system that functions as a pathogen recognition receptor (PRR) that recognizes pathogen-associated molecular patterns (PAMPs). NALP3 belongs to the NOD-like receptor (NLR) subfamily of PRRs and NALP3 together with the adaptor ASC protein PYCARD forms a caspase-1 activating complex known as the NALP3 inflammasome. NALP3 in the absence of activating signal is kept in an inactive state complexed with HSP90 and SGT1 in the cytoplasm. NALP3 inflammasome detects danger signals such as crystalline uric acid and extracellular ATP released by damaged cells. These signals release of HSP90 and SGT1 from and recruit ASC protein and caspase-1 to the inflammasome complex. Caspase-1 within the activated NALP3 inflammasome complex in turn activates the inflammatory cytokine, IL-1β.

The NALP3 inflammasome appears to be activated by changes in intracellular potassium caused by potassium efflux from mechanosensitive ion channels located in the cell membrane. It appears that that NALP3 is also regulated by reactive oxygen species (ROS), though the precise mechanisms of such regulation has not been determined.

Pathology

Mutations in the NLRP3 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).

Defects in this gene have also been linked to familial Mediterranean fever. In addition, the NALP3 inflammasome has a role in the pathogenesis of gout and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer's, Parkinson's, and Prion diseases.

Deregulation of NALP3 has been connected with carcinogenesis. For example, all the components of the NALP3 inflammasome are downregulated or completely lost in human hepatocellular carcinoma.