NLRP1 Gene: Inflammasome Sensor and Disease-Associated Variants
Comprehensive reference for NLRP1 (NALP1/CARD7), covering genomic context, protein function, expression, pathogenic variants, and associated inflammatory and neoplastic disorders.
Gene Information Card
| Symbol | NLRP1 |
|---|---|
| Full Name | NLR family pyrin domain containing 1 |
| Gene Type | protein coding |
| Chromosomal Location | 17p13.2 |
| NCBI Gene ID | 22861 ncbi.nlm.nih.gov/gene/22861 |
| Ensembl ID | ENSG00000091592 |
| UniProt ID | Q9C000 |
| OMIM ID | 606636 |
| HGNC ID | HGNC:14374 |
| Aliases | NALP1, CARD7, DEFCAP, NAC, PPPL1, CLR17.1 |
Description
The NLRP1 gene encodes a cytosolic pattern recognition receptor that is a key component of the innate immune system. It functions as a sensor for pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), leading to the assembly of a multi-protein complex called the inflammasome. Activation of the NLRP1 inflammasome triggers the proteolytic activation of pro-inflammatory caspases (CASP1), which in turn cleave pro-IL-1β and pro-IL-18 into their mature, secreted forms, and can also induce pyroptosis, a lytic form of cell death. NLRP1 is unique among NLRs due to the presence of a function-to-find domain (FIIND) that undergoes autoproteolytic processing, which is essential for its activation. Germline mutations in NLRP1 are associated with autoinflammatory syndromes and skin cancer susceptibility, while somatic alterations are observed in various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| NLRP1-associated autoinflammation with arthritis and dyskeratosis (NAIAD) | Gain-of-function mutations (e.g., p.Met770Thr, p.Arg726Trp) in the NACHT or LRR domains lead to constitutive or hyperactive inflammasome assembly, resulting in excessive IL-1β and IL-18 release and systemic inflammation. | OMIM #617034; ClinVar; PMID: 28114208 |
| Multiple self-healing palmoplantar carcinoma (MSPC) | Germline gain-of-function mutations (e.g., p.Met770Thr) in NLRP1 increase inflammasome activity in keratinocytes, promoting IL-1 signaling and skin tumorigenesis. | OMIM #615225; PMID: 26833330 |
| Familial keratosis lichenoides chronica (FKLC) | Heterozygous missense mutations (e.g., p.Arg726Trp) in NLRP1 cause hyperactivation of the inflammasome in skin, leading to chronic inflammatory skin lesions. | OMIM #612281; PMID: 28114208 |
| Vitiligo-associated multiple autoimmune disease susceptibility 1 | Specific NLRP1 variants (e.g., p.Leu155His) are associated with increased risk for vitiligo and other autoimmune conditions, likely through altered inflammasome regulation and IL-1β production. | OMIM #606579; PMID: 17637806 |
| Melanoma | Somatic copy number gains and missense mutations in NLRP1 are found in melanoma, potentially contributing to tumor-promoting inflammation and resistance to apoptosis. | COSMIC; PMID: 21720389 |
| Colorectal cancer | Somatic mutations and altered expression of NLRP1 have been reported, with some studies suggesting a role in tumor progression via modulation of the inflammatory microenvironment. | COSMIC; PMID: 26503515 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skin | 15.2 | Medium |
| Esophagus | 10.1 | Low |
| Lung | 8.5 | Low |
| Spleen | 7.8 | Low |
| Small Intestine | 6.9 | Low |
| Bone Marrow | 5.4 | Low |
| Liver | 4.2 | Low |
| Brain | 2.1 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HaCaT (keratinocyte) | 25.3 | High expression; relevant for skin cancer studies |
| A549 (lung carcinoma) | 12.8 | Moderate expression |
| MCF7 (breast carcinoma) | 8.1 | Low expression |
| HepG2 (hepatocellular carcinoma) | 5.2 | Low expression |
| K562 (leukemia) | 3.4 | Very low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Met770Thr | Missense (germline) | Rare (found in families with NAIAD/MSPC) | Gain-of-function; enhances inflammasome assembly and IL-1β secretion |
| p.Arg726Trp | Missense (germline) | Rare (found in families with NAIAD/FKLC) | Gain-of-function; increases NLRP1 oligomerization and activity |
| p.Leu155His | Missense (germline) | Polymorphic (minor allele frequency ~5-10%) | Hypomorphic; associated with vitiligo risk, possibly via altered regulation |
| p.Glu118Lys | Missense (somatic) | Sporadic (found in melanoma) | Unknown; may affect protein stability or interaction |
| p.Arg726Trp | Missense (somatic) | Sporadic (found in melanoma) | Gain-of-function; promotes tumor inflammation |
| Copy number gain (17p13.2) | Somatic CNV | Frequent in melanoma (~10-15%) | Increased gene dosage leading to higher NLRP1 expression |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in NLRP1 are rare and typically result in reduced inflammasome signaling. Complete loss of NLRP1 function in humans has not been clearly associated with a specific disease phenotype, likely due to redundancy with other NLRs. In vitro studies show that truncating mutations in the LRR domain can abrogate autoinhibition, but these are often gain-of-function in nature.
Gain of Function (GOF)
The majority of pathogenic NLRP1 mutations are gain-of-function. These mutations, often located in the NACHT domain (e.g., p.Met770Thr) or near the FIIND domain, disrupt autoinhibition, promote spontaneous oligomerization, and lead to constitutive activation of the inflammasome. This results in excessive IL-1β and IL-18 production, driving autoinflammation and tumor promotion in affected tissues.
Dominant Negative (DN)
Dominant-negative effects have been proposed for some NLRP1 variants, particularly those that disrupt the interaction with its inhibitor or prevent proper FIIND processing. However, clear dominant-negative mutations have not been definitively characterized in human disease. Some polymorphisms may act as partial dominant-negatives by forming non-functional oligomers with wild-type protein, but this requires further investigation.
View complete mutation data：
Gene Ontology (GO)
| • protein homodimerization activity | • ATP binding |
| • cysteine-type endopeptidase activator activity | • protein kinase binding |
| • inflammasome complex | • cytoplasm |
| • cytosol | • plasma membrane |
| • innate immune response | • inflammatory response |
| • regulation of inflammatory response | • positive regulation of interleukin-1 beta production |
| • positive regulation of cysteine-type endopeptidase activity | • pyroptosis |
| • signal transduction | • apoptotic process |
Pathways
• NOD-like receptor signaling pathway (KEGG: hsa04621)
• IL-1 signaling pathway (Reactome: R-HSA-446652)
• Inflammasome pathway (Reactome: R-HSA-622312)
• Pyroptosis (Reactome: R-HSA-5620971)
Protein Summary
The NLRP1 protein (UniProt Q9C000) is a 1473-amino acid multidomain protein. It contains an N-terminal pyrin domain (PYD), a NACHT domain (central nucleotide-binding domain), a NACHT-associated domain (NAD), a function-to-find domain (FIIND) that undergoes post-translational autoproteolysis, and a C-terminal leucine-rich repeat (LRR) domain. The PYD domain is involved in protein-protein interactions, while the NACHT domain mediates ATP-dependent oligomerization. The FIIND domain is critical for activation, as its autoproteolytic cleavage is required for the protein to adopt an active conformation. The LRR domain is thought to be involved in autoinhibition and ligand sensing. Upon activation, NLRP1 nucleates the assembly of the inflammasome complex with the adaptor protein ASC (PYCARD) and pro-caspase-1, leading to caspase-1 activation and subsequent cytokine maturation and pyroptosis.
Related Services
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| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NLRP11 Knockout HEK293 Cell Line | EDJ-KQ5976 | Human | 204801 | Details Get a Quote |
| NLRP1 Knockout HEK293 Cell Line | EDJ-KQ7700 | Human | 22861 | Details Get a Quote |
| NLRP13 Knockout HEK293 Cell Line | EDJ-KQ8867 | Human | 126204 | Details Get a Quote |
| NLRP12 Knockout HEK293 Cell Line | EDJ-KQ10770 | Human | 91662 | Details Get a Quote |
| NLRP10 Knockout HEK293 Cell Line | EDJ-KQ14440 | Human | 338322 | Details Get a Quote |
| NLRP14 Knockout HEK293 Cell Line | EDJ-KQ14441 | Human | 338323 | Details Get a Quote |
| NLRP1 Knockout HCT 116 Cell Line | EDJ-KQ33084 | Human | 22861 | Details Get a Quote |
| NLRP1 Knockout HeLa Cell Line | EDJ-KQ33085 | Human | 22861 | Details Get a Quote |
| NLRP11 Knockout HCT 116 Cell Line | EDJ-KQ29549 | Human | 204801 | Details Get a Quote |
| NLRP12 Knockout HeLa Cell Line | EDJ-KQ57808 | Human | 91662 | Details Get a Quote |
| NLRP13 Knockout HeLa Cell Line | EDJ-KQ58168 | Human | 126204 | Details Get a Quote |
| NLRP11 Knockout HeLa Cell Line | EDJ-KQ59054 | Human | 204801 | Details Get a Quote |
| NLRP10 Knockout HeLa Cell Line | EDJ-KQ59604 | Human | 338322 | Details Get a Quote |
| NLRP14 Knockout HeLa Cell Line | EDJ-KQ59605 | Human | 338323 | Details Get a Quote |
| NLRP1 Knockout A-549 Cell Line | EDJ-KQ64145 | Human | 22861 | Details Get a Quote |
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