Alt. symbols: NALP1 | SLEV1 | KIAA0926 | DKFZp586O1822 | CARD7 | NAC | CLR17.1 | DEFCAP | VAMAS1

Approved name: NLR family pyrin domain containing 1
Alt. names: NACHT, leucine rich repeat and PYD (pyrin domain) containing 1, systemic lupus erythematosus, vitiligo-related 1 | nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1

Location: 17p13.2: 5499415 - 5619424 (-)
Gene type: protein_coding, 70 transcripts.

Scores: LoFtool: 0.926000 | pLI: 0.00000000 | LOEUF: 0.836

HGNC: 14374 | Infevers

NCBI: 22861, RefSeq: NG_011651.1

Ensembl: ENSG00000091592.17

LRG_ | Status: none

OMIM: 606636

Expression | ProteinAtlas

Gene Ontology (GO)

• Molecular function:
• Cell component: canonical inflammasome complex [GO:0061702]
• Biological process:

Normal function

NLRP1 encodes the sensor component of the NLRP1 inflammasome, a polymeric complex that triggers an inflammatory process in response to pathogens and other damage-associated signals. NLRP1 is highly expressed in keratinocytes and hematopoietic cells, and senses UVB-dependent radiation damage, bacterial toxins and viral double stranded RNA (dsRNA) (PMID: 28733143). NLRP1 is unique among inflammasomes in that its C-terminal end is composed of a ‘function-to-find’ domain (FIIND) and a CARD domain, while its pyrin and LRR domains are thought to be autoinhibitory. FIIND autoproteolytic cleavage leads to CARD domain release and inflammasome activation (PMID: 22665479). The NLRP1 inflammasome then recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines such as IL-1beta and IL-18 and gasdermin-D (GSDMD), leading to pyroptosis (PMID: 22665479, 12191486, 17349957, 32051255, 33093214). Activation of NLRP1 inflammasome is also required for HMGB1 secretion; the active cytokines and HMGB1 stimulate inflammatory responses (PMID: 22801494).

Dysfunction and disease

Low penetrance coding and non-coding SNPs in NLRP1 have been associated with susceptibility to vitiligo and other autoimmune and autoinflammatory diseases [OMIM: 606579] (PMID: 23382179, 18946481, 17377159), while rare activating mutations have been associated with at least 3 distinct AR or AD Mendelian disorders on a spectrum of presentations from skin-restricted disease to systemic auto-inflammation. These conditions all appear to share a common underlying pathophysiology involving increased N LRP1 inflammasome activation leading to inflammation driven by caspase-1-dependent IL-1beta and IL-18 over-production (PMID: 31873740). Consistent with this pathophysiological mechanism, patients respond to treatments that reduce IL-1 secretion or inhibit IL-1 signaling (PMID: 32640751, 34035534). Two overlapping skin disorders with no features of systemic inflammation - multiple self-healing palmoplantar carcinoma (MSPC) [OMIM:615225] and familial keratosis lichenoides chronica (FKLC) - are associated with mono- or bi-allelic missense mutations (and 1 in-frame deletion) in the autoinhibitory N-terminal pyrin and LRR domains, respectively (PMID: 27662089). Heterozygous missense mutations in the pyrin domain have also been found in patients with dominantly-inherited inflammatory corneal dyskeratosis, often also accompanied by ectodermal and mucosal inflammation, manifesting as tooth abnormalities, nail dystrophy, dyshidrosis and voice changes [OMIM: 617388] (PMID: 23349227, 31873740). Mono- and bi-allelic missense mutations have been reported in patients with NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis) [MIM:617388] (PMID: 27965258), a systemic inflammatory condition affecting eyes, skin, joints and GI tract, but also with features suggestive of immunodeficiency and autoimmunity. In addition to very high levels of serum IL-1beta and IL-18, patients may show abnormalities on lymphocyte subsets, hypereosinophilia, hypergammaglobulinemia, and auto-antibody production. One patient with a de novo missense mutation located near the FIIND domain autoproteolytic cleavage site had particularly severe auto-inflammation (PMID: 27965258). In all these cases, disruption of the autoinhibitory function of these two domains was shown to cause constitutive NLRP1 self-oligomerization and inflammasome activation. Finally, a missense mutation in the linker connecting the NACHT and LRR domains was identified in 2 siblings with rare condition called juvenile-onset recurrent respiratory papillomatosis (JRRP), characterized by keratotic skin lesions and recurrent respiratory papillomas leading to potentially life-threatening airway obstructions [OMIM: 618803] (PMID: 31484767). [Load More]