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Details on Person UniProt:Q2LKU9 Nlrp1a
| Class:Id | ReferenceGeneProduct:8856995 |
|---|---|
| _chainChangeLog | chain:1-1182 added on Fri February 12 2016;chain:1-932 for 8856995 added on Wed August 11 2021;chain:933-1182 for 8856995 added on Wed August 11 2021 |
| _displayName | UniProt:Q2LKU9 Nlrp1a |
| _timestamp | 2023-11-03 15:09:59 |
| chain | chain:1-1182 chain:1-932 chain:933-1182 |
| checksum | D6D3F9FD5629D44A |
| comment | FUNCTION Acts as the sensor component of the Nlrp1a inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis (PubMed:23219391). 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 (By similarity). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, and mediates the formation of the inflammasome polymeric complex (By similarity). In response to pathogen-associated signals, the N-terminal part of Nlrp1a is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), which polymerizes to initiate the formation of the inflammasome complex: the 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 (By similarity). In the absence of GSDMD expression, the Nlrp1a inflammasome is able to recruit and activate CASP8, leading to activation of gasdermin-E (GSDME) (By similarity). Activation of Nlrp1a inflammasome is also required for HMGB1 secretion; the active cytokines and HMGB1 stimulate inflammatory responses (By similarity). When activated in the bone marrow, induces the pyroptosis of hematopoietic stem cells and progenitor cells of both myeloid and lymphoid lineages, hence allowing the removal of damaged cells, and the release of IL1B, which induces granulopoiesis (PubMed:23219391).FUNCTION Constitutes the precursor of the Nlrp1a 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.FUNCTION Regulatory part that prevents formation of the Nlrp1a inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), preventing activation of the Nlrp1a inflammasome (By similarity). 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 Nlrp1a inflammasome (By similarity).FUNCTION Constitutes the active part of the Nlrp1a inflammasome (By similarity). In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, N-terminus), preventing activation of the Nlrp1a inflammasome (By similarity). In response to pathogen-associated signals, the N-terminal part of Nlrp1a is degraded by the proteasome, releasing this form, which polymerizes to form the Nlrp1a inflammasome complex: the Nlrp1a inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis (By similarity).ACTIVITY REGULATION Nlrp1a inflammasome is activated by pathogens and other damage-associated signals: activation promotes ubiquitination and degradation of the N-terminal part, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), which polymerizes and forms the Nlrp1a inflammasome (By similarity). Nlrp1a inflammasome is inhibited by DPP8 and DPP9, which sequester the C-terminal fragment of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus) in a ternary complex, thereby preventing Nlrp1a oligomerization and activation (By similarity). Nlrp1a inflammasome is activated by Val-boroPro (Talabostat, PT-100), an inhibitor of dipeptidyl peptidases DPP8 and DPP9 (PubMed:31383852). Val-boroPro relieves inhibition of DPP8 and/or DPP9 by promoting disruption of the ternary complex, releasing its C-terminal part from autoinhibition (By similarity).SUBUNIT Interacts (via LRR repeats) with BCL2 and BCL2L1 (via the loop between motifs BH4 and BH3) (By similarity). Interacts with NOD2; this interaction is enhanced in the presence of muramyl dipeptide (MDP) and increases IL1B release (By similarity). Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to danger-associated signals (By similarity). Interacts with MEFV; this interaction targets Nlrp1a to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (By similarity). Interacts with DPP9; leading to inhibit activation of the inflammasome (By similarity). DPP9 acts via formation of a ternary complex, composed of a DPP9 homodimer, one full-length Nlrp1a protein, and one cleaved C-terminus of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus) (By similarity). Interacts with DPP8; leading to inhibit activation of the inflammasome, probably via formation of a ternary complex with DPP8 (By similarity).SUBUNIT Interacts with the C-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus) in absence of pathogens and other damage-associated signals.SUBUNIT Interacts with the N-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, N-terminus) in absence of pathogens and other damage-associated signals (By similarity). Homomultimer; forms the Nlrp1a inflammasome polymeric complex, a filament composed of homopolymers of this form in response to pathogens and other damage-associated signals (By similarity). Interacts (via CARD domain) with CASP1 (via CARD domain); leading to CASP1 activation (By similarity).SUBCELLULAR LOCATION Nucleocytoplasmic distribution in lymphoid organs (probably in T-cells) and in neurons. In epithelial cells, predominantly cytoplasmic.SUBCELLULAR LOCATION Highly expressed in hematopoietic stem cells and progenitor cells of both myeloid and lymphoid origin (PubMed:23219391). The expression is highly strain-dependent. Not expressed in Balb/cJ animals, but widely expressed in C57BL/6J. Expressed in macrophages resistant to Bacillus anthracis lethal toxin, but not in toxin-sensitive macrophages, except in CAST/EiJ strain (PubMed:23506131).DOMAIN 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.DOMAIN The FIIND (domain with function to find) region is involved in homomerization, but not in CASP1-binding. Autocatalytic cleavage in this region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding. Both N- and C-terminal fragments remain associated.DOMAIN The C-terminal part of Nlrp1a oligomerizes to form the core of the Nlrp1a 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. The UPA region reduces the threshold needed for filament formation and signaling.PTM Autocatalytically cleaved. Autocatalytic cleavage in FIIND region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding. Both N- and C-terminal parts remain associated non-covalently.PTM Ubiquitinated 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 1a, C-terminus), which polymerizes and forms the Nlrp1a inflammasome.MISCELLANEOUS Three tandem Nrlp1 paralogs, Nrlp1a, Nrlp1b and Nrlp1c, are present in at least 2 strains, C57BL/6J and 129S1/SvImJ. Nlrp1c is predicted to be a pseudogene. Nlrp1b is the primary mediator of macrophage susceptibility to Bacillus anthracis lethal toxin (LT). Neither Nlrp1a, nor Nrlp1c are expressed in anthrax lethal toxin susceptible strains, hence neither of them is thought to play an important role in this phenotype.SIMILARITY Belongs to the NLRP family. |
| created | [InstanceEdit:8856987] Weiser, JD |
| description | recommendedName: NACHT, LRR and PYD domains-containing protein 1a ecNumber evidence="2"3.4.-.- alternativeName: Caspase recruitment domain-containing protein 7 alternativeName: Death effector filament-forming ced-4-like apoptosis protein alternativeName: Nucleotide-binding domain and caspase recruitment domain component recommendedName: fullName evidence="11"NACHT, LRR and PYD domains-containing protein 1a, C-terminus shortName evidence="2"Nlrp1a-CT /component component recommendedName: fullName evidence="11"NACHT, LRR and PYD domains-containing protein 1a, N-terminus shortName evidence="2"Nlrp1a-NT /component |
| geneName | Nlrp1a Card7 Nalp1 Nalp1a Nlrp1 |
| identifier | Q2LKU9 |
| isSequenceChanged | FALSE |
| keyword | Alternative splicing ATP-binding Cytoplasm Hydrolase Immunity Inflammasome Inflammatory response Innate immunity Leucine-rich repeat Necrosis Nucleotide-binding Nucleus Protease Reference proteome Repeat Ubl conjugation |
| modified | [InstanceEdit:9037114] Weiser, JD [InstanceEdit:9637257] Weiser, JD [InstanceEdit:9657908] Weiser, JD [InstanceEdit:9676415] Weiser, JD [InstanceEdit:9715482] Weiser, JD [InstanceEdit:9750299] Weiser, JD [InstanceEdit:9773244] Weiser, Joel [InstanceEdit:9829221] Weiser, Joel [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 |
| name | Nlrp1a |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| secondaryIdentifier | NLR1A_MOUSE M4T3K8 M4T4C8 M4T632 M4TJP5 Q3U0B5 Q67EY4 |
| sequenceLength | 1182 |
| species | [Species:48892] Mus musculus |
| (isoformParent) | [ReferenceIsoform:8856996] UniProt:Q2LKU9-1 Nlrp1a [Mus musculus] [ReferenceIsoform:8856997] UniProt:Q2LKU9-2 Nlrp1a [Mus musculus] |
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No pathways have been reviewed or authored by UniProt:Q2LKU9 Nlrp1a (8856995)
