NALP3

NLRP3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3QF2, 2NAQ
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
External IDs	OMIM: 606416 MGI: 2653833 HomoloGene: 3600 GeneCards: NLRP3
Gene ontology Molecular function • sequence-specific DNA binding • nucleotide binding • transcription factor binding • protein binding • peptidoglycan binding • ATP binding Cellular component • cytoplasm • NLRP3 inflammasome complex • cytosol • extracellular region • endoplasmic reticulum • inflammasome complex • nucleus Biological process • defense response • detection of biotic stimulus • NLRP3 inflammasome complex assembly • regulation of transcription, DNA-templated • negative regulation of acute inflammatory response • positive regulation of interleukin-5 production • interleukin-1 secretion • interleukin-18 production • immune system process • positive regulation of interleukin-4 production • transcription, DNA-templated • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process • positive regulation of interleukin-13 production • positive regulation of T-helper 17 cell differentiation • positive regulation of NF-kappaB transcription factor activity • defense response to virus • protein oligomerization • positive regulation of interleukin-1 beta secretion • positive regulation of T-helper 2 cell differentiation • regulation of inflammatory response • interleukin-1 beta production • positive regulation of type 2 immune response • inflammatory response • negative regulation of NF-kappaB transcription factor activity • activation of cysteine-type endopeptidase activity involved in apoptotic process • negative regulation of NF-kappaB import into nucleus • negative regulation of inflammatory response • cellular response to lipopolysaccharide • negative regulation of interleukin-1 beta secretion • positive regulation of T-helper 2 cell cytokine production • signal transduction • positive regulation of transcription from RNA polymerase II promoter • apoptotic process • innate immune response Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	114548	216799
Ensembl	ENSG00000162711	ENSMUSG00000032691
UniProt	Q96P20	Q8R4B8
RefSeq (mRNA)	NM_001079821 NM_001127461 NM_001127462 NM_001243133 NM_004895 NM_183395	NM_145827
RefSeq (protein)	NP_001073289.1 NP_001120933.1 NP_001120934.1 NP_001230062.1 NP_004886.3 NP_899632.1	NP_665826.1
Location (UCSC)	Chr 1: 247.42 – 247.45 Mb	Chr 11: 59.54 – 59.57 Mb
PubMed search	[1]	[2]
Wikidata

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^[3] located on the long arm of chromosome 1.^[4]

NALP3 is expressed predominantly in macrophages and as a component of the inflammasome,^[5][6]:436 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 with 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" ^[7][8] and is synonymous with NLR, for or nucleotide-binding domain, leucine-rich repeat"^[9]
• PYD – "PYRIN domain," after the pyrin proteins^[10] The NLRP3 gene name abbreviates "NLR family, pyrin domain containing 3," where NLR refers to "nucleotide-binding domain, leucine-rich repeat."^[11]

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).^[12]

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.^[3]

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).^[13] 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.^[13]

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.^[14] It appears that that NALP3 is also regulated by reactive oxygen species (ROS), though the precise mechanisms of such regulation has not been determined.^[15]

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).^[3]

Defects in this gene have also been linked to familial Mediterranean fever.^[16] In addition, the NALP3 inflammasome has a role in the pathogenesis of gout^[13] and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer's, Parkinson's, and Prion diseases.^[17][18][19]

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.^[20]

References and notes

Further reading