DegronMD - Q9C000(NLRP1)

FUNCTION: 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:22665479, PubMed:12191486, PubMed:17349957, PubMed:27662089, PubMed:31484767, PubMed:33093214, PubMed:33731929, PubMed:33731932). 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:22665479, PubMed:12191486, PubMed:17349957). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as cleavage by human rhinoviruses 14 and 16 (HRV-14 and HRV-16), double-stranded RNA or Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex composed of NLRP1, CASP1 and PYCARD/ASC (PubMed:22665479, PubMed:12191486, PubMed:17349957, PubMed:30291141, PubMed:33243852, PubMed:33093214). 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:22665479, PubMed:12191486, PubMed:17349957, PubMed:32051255, PubMed:33093214). 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). {ECO:0000269|PubMed:11113115, ECO:0000269|PubMed:12191486, ECO:0000269|PubMed:15212762, ECO:0000269|PubMed:17349957, ECO:0000269|PubMed:18511561, ECO:0000269|PubMed:22665479, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:27662089, ECO:0000269|PubMed:30291141, ECO:0000269|PubMed:31484767, ECO:0000269|PubMed:32051255, ECO:0000269|PubMed:33093214, ECO:0000269|PubMed:33243852, ECO:0000269|PubMed:33731929, ECO:0000269|PubMed:33731932}.; FUNCTION: [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. {ECO:0000269|PubMed:22087307}.; FUNCTION: [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). {ECO:0000269|PubMed:33093214}.; FUNCTION: [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). {ECO:0000269|PubMed:33093214, ECO:0000269|PubMed:33731929, ECO:0000269|PubMed:33731932}.; FUNCTION: [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). {ECO:0000269|PubMed:17349957, ECO:0000269|PubMed:22665479}. View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.G184W	TCGA-53-7626	LUAD	TCGA	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.2222
p.G184W	TCGA-D3-A2JC	SKCM	TCGA	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.2222
p.G184W	DO23774	LUAD	ICGC	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.2222
p.G184W	DO47578	SKCM	ICGC	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.2222
p.S188F	TCGA-D9-A6EC	SKCM	TCGA	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.1111
p.S188F	DO50291	SKCM	ICGC	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.1111
p.G187E	TCGA-EE-A29D	SKCM	TCGA	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.1389
p.G187E	DO38123	SKCM	ICGC	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.1389
p.W186C	TCGA-EE-A29L	SKCM	TCGA	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.1667
p.W186C	DO37835	SKCM	ICGC	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.1667
p.P177A	TCGA-N7-A4Y5	UCS	TCGA	APTST	DEG_SPOP_SBC_1	176:180	Mutation altering degron motif	0.6392
p.A176T	TCGA-OL-A5RU	BRCA	TCGA	APTST	DEG_SPOP_SBC_1	176:180	Mutation altering degron motif	0.7139
p.A176T	DO44196	BRCA	ICGC	APTST	DEG_SPOP_SBC_1	176:180	Mutation altering degron motif	0.7139
p.P177T	DO229032	LICA	ICGC	APTST	DEG_SPOP_SBC_1	176:180	Mutation altering degron motif	0.5919
p.P190T	DO229038	LICA	ICGC	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.0556
p.P189A	DO44868	LICA	ICGC	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.0833
p.N175S	DO228338	MALY	ICGC	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.3056
p.N175S	SIDM00948	Burkitt's Lymphoma	GDSC	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.3056
p.N175S	ACH-002232	Lymphoma	CCLE	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.3056
p.N175S	DG-75	haematopoietic and lymphoid tissue	COSMIC	APTST	DEG_SPOP_SBC_1	176:180	Mutation rewiring degron network	0.3056

DegronMD: protein-targeted degradation, mutation and drug response to degrons

NLRP1

UniProt ID: Q9C000

Entrez ID: 22861

External links: UniprotKB HGNC RefSeq COSMIC

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