Associated with differentiation in stratified epithelia of the skin, esophagus, intestine, and cervix, as well as in the prostate gland. Undetectable in undifferentiated basal cells, but expressed in differentiated luminal secretory cells (PubMed:11113115). Expressed in differentiated macrophages and granulocytes, but not their precursors (at protein level) (PubMed:11113115, PubMed:15285719). In testis, also associated with cell differentiation, with conflicting results. Expressed in spermatogonia and primary spermatocytes, but not in cells from later differentiation stages, including secondary spermatocytes, spermatids, and spermatozoa (at protein level) (PubMed:17164409). Not detected in spermatocytes, nor spermatids, and strongly expressed in spermatozoa (at protein level) (PubMed:11113115).
The CARD domain, rather than the pyrin domain, is involved in the interaction with PYCARD, CASP1 and CASP5.
The ZAKalpha motifs are recognized and phosphorylated by isoform ZAKalpha of MAP3K20.
The leucine-rich repeat (LRR) domain may be involved in autoinhibition in the absence of activating signal, possibly through intramolecular interaction with the NACHT domain. Serves as the predominant binding domain for dsRNA and dsDNA (PubMed:33243852).
The FIIND (domain with function to find) region is involved in homomerization, but not in CASP1-binding (By similarity). Autocatalytic cleavage in this region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding (PubMed:22087307, PubMed:22665479). Both N- and C-terminal fragments remain associated (PubMed:22087307, PubMed:22665479).
The pyrin domain mediates an autoinhibitory function, potentially acting as a threshold modulator, which allows NLRP1 to discriminate long from short dsRNA. Inhibits ATPase activity of the NATCH domain.
NACHT, LRR and PYD domains-containing protein 1, C-terminus
The C-terminal part of NLRP1 oligomerizes to form the core of the NLRP1 inflammasome filament: in the filament, the CARD domains form a central helical filaments that are promoted by oligomerized, but flexibly linked, UPA regions surrounding the filaments (PubMed:33420028, PubMed:33420033). The UPA region reduces the threshold needed for filament formation and signaling (PubMed:33420028, PubMed:33420033). Must recruit the adapter PYCARD/ASC to facilitate CASP1 interaction and polymerization (PubMed:33420033).
Upon dsRNA-binding via its LRR domain, NACHT domain gains ATPase activity which is inhibited by the pyrin domain.
Acts as the sensor component of the NLRP1 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis (PubMed:12191486, PubMed:17349957, PubMed:22665479, PubMed:27662089, PubMed:31484767, PubMed:33093214, PubMed:33410748, PubMed:33731929, PubMed:33731932, PubMed:35857590). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:12191486, PubMed:17349957, PubMed:22665479). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as cleavage by some human enteroviruses and rhinoviruses, double-stranded RNA, UV-B irradiation, or Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex composed of NLRP1, CASP1 and PYCARD/ASC (PubMed:12191486, PubMed:17349957, PubMed:22665479, PubMed:25562666, PubMed:30096351, PubMed:30291141, PubMed:33093214, PubMed:33243852, PubMed:33410748, PubMed:35857590). In response to pathogen-associated signals, the N-terminal part of NLRP1 is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and associates with PYCARD/ASC to initiate the formation of the inflammasome complex: the NLRP1 inflammasome recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (PubMed:12191486, PubMed:17349957, PubMed:22665479, PubMed:32051255, PubMed:33093214). In the absence of GSDMD expression, the NLRP1 inflammasome is able to recruit and activate CASP8, leading to activation of gasdermin-E (GSDME) (PubMed:33852854, PubMed:35594856). Activation of NLRP1 inflammasome is also required for HMGB1 secretion; the active cytokines and HMGB1 stimulate inflammatory responses (PubMed:22801494). Binds ATP and shows ATPase activity (PubMed:11113115, PubMed:15212762, PubMed:33243852). Plays an important role in antiviral immunity and inflammation in the human airway epithelium (PubMed:33093214). Specifically recognizes a number of pathogen-associated signals: upon infection by human rhinoviruses 14 and 16 (HRV-14 and HRV-16), NLRP1 is cleaved and activated which triggers NLRP1-dependent inflammasome activation and IL18 secretion (PubMed:33093214). Positive-strand RNA viruses, such as Semliki forest virus and long dsRNA activate the NLRP1 inflammasome, triggering IL1B release in a NLRP1-dependent fashion (PubMed:33243852). Acts as a direct sensor for long dsRNA and thus RNA virus infection (PubMed:33243852). May also be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner (PubMed:18511561). The NLRP1 inflammasome is also activated in response to UV-B irradiation causing ribosome collisions: ribosome collisions cause phosphorylation and activation of NLRP1 in a MAP3K20-dependent manner, leading to pyroptosis (PubMed:35857590).
NACHT, LRR and PYD domains-containing protein 1
Constitutes the precursor of the NLRP1 inflammasome, which mediates autoproteolytic processing within the FIIND domain to generate the N-terminal and C-terminal parts, which are associated non-covalently in absence of pathogens and other damage-associated signals.
NACHT, LRR and PYD domains-containing protein 1, N-terminus
Regulatory part that prevents formation of the NLRP1 inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus), preventing activation of the NLRP1 inflammasome (PubMed:33093214). In response to pathogen-associated signals, this part is ubiquitinated and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the NLRP1 inflammasome (PubMed:33093214).
NACHT, LRR and PYD domains-containing protein 1, C-terminus
Constitutes the active part of the NLRP1 inflammasome (PubMed:33093214, PubMed:33731929, PubMed:33731932). In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, N-terminus), preventing activation of the NLRP1 inflammasome (PubMed:33093214). In response to pathogen-associated signals, the N-terminal part of NLRP1 is degraded by the proteasome, releasing this form, which polymerizes and associates with PYCARD/ASC to form of the NLRP1 inflammasome complex: the NLRP1 inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis (PubMed:33093214).
Isoform 2
It is unclear whether is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release (PubMed:22665479). However, in an vitro cell-free system, it has been shown to be activated by MDP (PubMed:17349957).
Vitiligo-associated multiple autoimmune disease 1
VAMAS1
A disorder characterized by the association of vitiligo with several autoimmune and autoinflammatory diseases including autoimmune thyroid disease, rheumatoid arthritis and systemic lupus erythematosus.
None
Disease susceptibility is associated with variants affecting the gene represented in this entry.
Palmoplantar carcinoma, multiple self-healing
MSPC
An autosomal dominant disease characterized by keratopathy with neovascularization, bilateral corneal opacification, palmoplantar hyperkeratosis, dyshidrosis, dystrophic nails, and recurrent keratoacanthomas in palmoplantar skin as well as in conjunctival and corneal epithelia. In addition, patients experience a high susceptibility to malignant squamous cell carcinoma.
None
The disease is caused by variants affecting the gene represented in this entry.
Autoinflammation with arthritis and dyskeratosis
AIADK
A disorder characterized by recurrent fever, diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Inheritance can be autosomal dominant or autosomal recessive.
None
The disease may be caused by variants affecting the gene represented in this entry.
Respiratory papillomatosis, juvenile recurrent, congenital
JRRP
An autosomal recessive disease characterized by recurrent growth of papillomas in the respiratory tract, and onset in early childhood. Papillomas are most commonly found in the larynx but may occur anywhere from the mouth to the bronchi. Children typically present within the first years of life with hoarseness or, in more severe cases, respiratory distress or stridor and airway obstruction. JRRP is associated with infection of the upper airway by human papillomaviruses of the alpha genus. The infection is thought to occur by vertical transmission at birth.
None
The disease may be caused by variants affecting the gene represented in this entry.
NACHT, LRR and PYD domains-containing protein 1
Autocatalytically cleaved (PubMed:22087307, PubMed:22665479, PubMed:33093214). Autocatalytic cleavage in FIIND region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding (PubMed:22087307, PubMed:22665479, PubMed:33093214). Both N- and C-terminal parts remain associated non-covalently (PubMed:22087307, PubMed:22665479, PubMed:33093214).
NACHT, LRR and PYD domains-containing protein 1, N-terminus
Ubiquitinated by the cullin:ZER1/ZYG11B complex in response to pathogen-associated signals, leading to its degradation by the proteasome and subsequent release of the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and forms the NLRP1 inflammasome.
Phosphorylated by MAP3K20 isoform ZAKalpha, MAPK11 and MAPK14 in response to UV-B irradiation and ribosome collisions, promoting activation of the NLRP1 inflammasome and pyroptosis.
(Microbial infection) Cleaved between Gln-130 and Gly-131 by the Protease 3C from various human enteroviruses and rhinoviruses (EV68, EV71, Coxsackievirus B3, HRV-14 and HRV-16) (PubMed:33093214, PubMed:33410748). This cleavage triggers N-glycine-mediated proteasomal degradation of the autoinhibitory NLRP1 N-terminal fragment via the cullin:ZER1/ZYG11B complex which liberates the activating C-terminal fragment and activates NLRP1 inflammasome (PubMed:33093214).
(Microbial infection) Cleaved between Gln-333 and Gly-334 by the 3C-like proteinase nsp5 from human coronavirus SARS-CoV-2 (PubMed:35594856). This cleavage liberates the activating C-terminal fragment and activates NLRP1 inflammasome, leading to downstream activation of GSDME and lung epithelial cell death (PubMed:35594856).
Belongs to the NLRP family.
Widely expressed (PubMed:11113115, PubMed:17164409). Abundantly expressed in primary immune cells (isoform 1 and isoform 2), including in neutrophils, monocytes/macrophages, dendritic cells (mostly Langerhans cells), and B- and T-lymphocytes (at protein level) (PubMed:15285719, PubMed:17164409). Strongly expressed in epithelial cells lining the glandular epithelium, such as that of the gastrointestinal tract (stomach, small intestine, colon), the respiratory tract (trachea and bronchi), and the endometrial and endocervical glands, gallbladder, prostate, and breast (at protein level). In testis, expressed in spermatogonia and primary spermatocytes, but not in Sertoli cells (at protein level). In the brain, expressed in neurons, in particular in pyramidal ones and in oligodendrocytes, but not detected in microglia (at protein level) (PubMed:17164409). Expressed in adult and fetal ocular tissues, including in adult and 24-week old fetal choroid, sclera, cornea, and optic nerve, as well as in adult retina and fetal retina/retinal pigment epithelium (PubMed:23349227). Highly expressed in the skin throughout the epidermis and in dermal fibroblasts, in both glabrous skin and plantar skin. It is detected in keratinocytes, but not in melanocytes. Expressed in epidermal appendages such as hair follicles (PubMed:27662089).
CARD7, DEFCAP, KIAA0926, NAC, NALP1, NLRP1, Caspase recruitment domain-containing protein 7, Death effector filament-forming ced-4-like apoptosis protein, Nucleotide-binding domain and caspase recruitment domain
Proteins
Immunology & Infectious Disease
165866Da
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