| IED ID | IndEnz0002007930 |
| Enzyme Type ID | protease007930 |
| Protein Name |
NACHT, LRR and PYD domains-containing protein 1b allele 1 EC 3.4.-.- Cleaved into: NACHT, LRR and PYD domains-containing protein 1b, C-terminus Nlrp1b1-CT ; NACHT, LRR and PYD domains-containing protein 1b, N-terminus Nlrp1b1-NT |
| Gene Name | Nlrp1b Nalp1b |
| Organism | Mus musculus (Mouse) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MEESPPKQKSNTKVAQHEGQQDLNTTRHMNVELKHRPKLERHLKLGMIPVVYMKQGEEILYPAQSLREENLIQNFTSLLLLQKLCPKDPENMIRKSWASCVPEEGGHMINIQDLFGPNIGTQKEPQLVIIEGAAGIGKSTLARLVKRAWKEGQLYRDHFQHVFFFSCRELAQCKKLSLAELIAQGQEVPTAPINQILSHPEKLLFILDGIDEPAWVLADQNPELCLHWSQRQPVHTLLGSLLGKSILPEAFFLLTTRTTALQKFIPSLPMPCQVEVLGFSGIERENYFYKYFANQRHAITAFMMVESNPVLLTLCEVPWVCWLVCTCLKKQMEQGRVLSLKSQTTTALCLKYLSLTIPDKHRRTQVKALCSLAAEGIWKRRTLFSESDLCKQGLDEDAVATFLKTGVLQKQASSLSYSFAHLCLQEFFAAISCILEDSEERHGNMEMDRIVETLVERYGRQNLFEAPTVRFLFGLLGKEGVKGMEKLFSCSLHGKTNLKLLWHILVKSQPHQPPCLGLLHCLYENQDMELLTHVMHDLQGTIVPGPNDTAHTVLQTNVKHLVVQTDMELMVATFCIQFYCHVRTLQLNMEKQQGYALISPRMVLYRWTPITNASWEILFYNLKFTRNLEGLDLSGNSLRYSVVQSLCNTLRYPGCQLKTLWLVKCGLTSRYCSLLASVLSAHSSLTELYLQLNDLGDDGVRMLCEGLRNPVCNLSILWLDLSSLSAQVITELRTLEEKNPKLYIRSIWMPHMMVPTENMDEEAILTTLKQQRQESGDKPMEILGTEEDFWGPTGPVATELVDRVRNLYRMPQMMVPTENMDEEDILTSFKQQRQQSGANPMEILGTEEDFWGPIGPVATEVVYRERNLYRVQLPMAGSYHCPSTRLHFVVTRAVTIEIEFCAWSQFLDKTPLQQSHMVVGPLFDIKAEQGAVTAVYLPHFVSLKDTKASTFDFKVAHFQEHGMVLETPDRVKPGYTVLKNPSFSPMGVVLRIIPAARHFIPITSITLIYYRVNQEEVTLHLYLVPNDCTIQKAIDDEEMKFQFVRINKPPPVDNLFIGSRYIVSGSENLEITPKELELCYRSSKEFQLFSEIYVGNMGSEIKLQIKNKKHMKLIWEALLKPGDLRPALPRIAQALKDAPSLLHFMDQHREQLVARVTSVDPLLDKLHGLVLNEESYEAVRAENTNQDKMRKLFNLSRSWSRACKDLFYQALKETHPHLVMDLLEKSGGVSLGS |
| Enzyme Length | 1233 |
| Uniprot Accession Number | Q2LKW6 |
| Absorption | |
| Active Site | |
| Activity Regulation | ACTIVITY REGULATION: Activated by cleavage by B.anthracis lethal toxin (LT) endopeptidase: cleavage by LT 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 1b, C-terminus), which polymerizes and forms the Nlrp1b inflammasome (PubMed:19124602, PubMed:19651869, PubMed:19949100, PubMed:22536155, PubMed:23818853, PubMed:24492532, PubMed:24935976, PubMed:31383852, PubMed:30872531). Activated by S.flexneri IpaH7.8, an E3 ubiquitin ligase that mediates ubiquitination and degradation of the N-terminal part, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the Nlrp1b inflammasome (PubMed:30872533). Nlrp1b inflammasome is inhibited by DPP8 and DPP9, which sequester the C-terminal fragment of Nlrp1b (NACHT, LRR and PYD domains-containing protein 1b, C-terminus) in a ternary complex, thereby preventing Nlrp1b oligomerization and activation (PubMed:29396289, PubMed:31525884). Nlrp1b inflammasome is activated by Val-boroPro (Talabostat, PT-100), an inhibitor of dipeptidyl peptidases DPP8 and DPP9 (PubMed:29396289, PubMed:31525884, PubMed:31383852, PubMed:30872531). 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). Activated by metabolic inhibitors, such as 2-deoxy-D-glucose and sodium azide, by nutrient deprivation and hypoxia, possibly due to a decrease in cytosolic ATP (PubMed:24935976, PubMed:23230290). Also activated by Toxoplasma gondii (PubMed:24218483). Not activated by muramyl dipeptide, nor by full-length bacterial peptidoglycan (PubMed:22753929). Contrary to its human ortholog, not activated by positive-strand RNA virus such as Semliki Forrest virus or long dsRNA (PubMed:33243852). {ECO:0000250|UniProtKB:Q9C000, ECO:0000269|PubMed:19124602, ECO:0000269|PubMed:19651869, ECO:0000269|PubMed:19949100, ECO:0000269|PubMed:22536155, ECO:0000269|PubMed:22753929, ECO:0000269|PubMed:23230290, ECO:0000269|PubMed:23818853, ECO:0000269|PubMed:24218483, ECO:0000269|PubMed:24492532, ECO:0000269|PubMed:24935976, ECO:0000269|PubMed:29396289, ECO:0000269|PubMed:30872531, ECO:0000269|PubMed:30872533, ECO:0000269|PubMed:31383852, ECO:0000269|PubMed:31525884, ECO:0000269|PubMed:33243852}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | 3.4.-.- |
| Enzyme Function | FUNCTION: Acts as the sensor component of the Nlrp1b inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis (PubMed:19651869, PubMed:21170303, PubMed:22536155, PubMed:22753929, PubMed:23818853). 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:19651869, PubMed:21170303, PubMed:22536155, PubMed:22753929, PubMed:23818853, PubMed:31268597, PubMed:30872533, PubMed:30872531). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as B.anthracis lethal toxin (LT) or Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex (PubMed:31268597, PubMed:30872533, PubMed:30872531). In response to pathogen-associated signals, the N-terminal part of Nlrp1b is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1b, C-terminus), which polymerizes to initiate the formation of the inflammasome complex: the inflammasome directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (PubMed:16429160, PubMed:19949100, PubMed:22753929, PubMed:23818853, PubMed:31268597, PubMed:30872533, PubMed:30872531). Activation of Nlrp1b inflammasome is also required for HMGB1 secretion; the active cytokines and HMGB1 stimulate inflammatory responses (PubMed:22801494). Primary mediator of macrophage susceptibility to B.anthracis LT: in response to B.anthracis infection, macrophages and dendritic cells release IL1B and undergo pyroptosis (PubMed:16429160, PubMed:19949100, PubMed:22753929, PubMed:23818853). This early inflammatory response to the toxin increases resistance to infection by B.anthracis spores (PubMed:16429160, PubMed:19949100, PubMed:22753929, PubMed:23818853). {ECO:0000269|PubMed:16429160, ECO:0000269|PubMed:19651869, ECO:0000269|PubMed:19949100, ECO:0000269|PubMed:21170303, ECO:0000269|PubMed:22536155, ECO:0000269|PubMed:22753929, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:23818853, ECO:0000269|PubMed:30872531, ECO:0000269|PubMed:30872533, ECO:0000269|PubMed:31268597}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1b allele 1]: Constitutes the precursor of the Nlrp1b 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:0000305|PubMed:23818853}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1b, N-terminus]: Regulatory part that prevents formation of the Nlrp1b inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of Nlrp1b (NACHT, LRR and PYD domains-containing protein 1b, C-terminus), preventing activation of the Nlrp1b inflammasome (PubMed:30872533, PubMed:30872531). In response to pathogen-associated signals, this part is ubiquitinated by the N-end rule pathway and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the Nlrp1b inflammasome (PubMed:30872533, PubMed:30872531). {ECO:0000269|PubMed:30872531, ECO:0000269|PubMed:30872533}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1b, C-terminus]: Constitutes the active part of the Nlrp1b inflammasome (PubMed:30872533, PubMed:30872531). In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of Nlrp1b (NACHT, LRR and PYD domains-containing protein 1b, N-terminus), preventing activation of the Nlrp1b inflammasome (PubMed:30872533, PubMed:30872531). In response to pathogen-associated signals, the N-terminal part of Nlrp1b is degraded by the proteasome, releasing this form, which polymerizes to form the Nlrp1b inflammasome complex: the Nlrp1b 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:31268597, PubMed:30872533, PubMed:30872531). {ECO:0000269|PubMed:30872531, ECO:0000269|PubMed:30872533, ECO:0000269|PubMed:31268597}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 132..139; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00136 |
| Features | Chain (3); Compositional bias (1); Domain (3); Mutagenesis (49); Nucleotide binding (1); Region (3); Repeat (2); Site (3) |
| Keywords | ATP-binding;Cytoplasm;Hydrolase;Immunity;Inflammasome;Inflammatory response;Innate immunity;Leucine-rich repeat;Membrane;Necrosis;Nucleotide-binding;Protease;Repeat;Ubl conjugation |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19124602}. Cytoplasm, cytosol {ECO:0000269|PubMed:19124602}. Membrane {ECO:0000269|PubMed:19124602}.; SUBCELLULAR LOCATION: [NACHT, LRR and PYD domains-containing protein 1b, C-terminus]: Inflammasome {ECO:0000269|PubMed:24492532, ECO:0000269|PubMed:30872533}. |
| Modified Residue | |
| Post Translational Modification | PTM: [NACHT, LRR and PYD domains-containing protein 1b allele 1]: Autocatalytically cleaved (PubMed:23818853). 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 (PubMed:23818853). {ECO:0000269|PubMed:23818853}.; PTM: [NACHT, LRR and PYD domains-containing protein 1b, N-terminus]: Ubiquitinated by UBR2, a component of the N-end rule pathway in response to pathogens and other damage-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 1b, C-terminus), which polymerizes and forms the Nlrp1b inflammasome. {ECO:0000269|PubMed:30872531, ECO:0000269|PubMed:31268597}.; PTM: [NACHT, LRR and PYD domains-containing protein 1b, N-terminus]: (Microbial infection) Cleavage by B.anthracis lethal toxin (LT) endopeptidase 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 1b, C-terminus), which polymerizes and forms the Nlrp1b inflammasome. {ECO:0000269|PubMed:19124602, ECO:0000269|PubMed:19651869, ECO:0000269|PubMed:19949100, ECO:0000269|PubMed:22536155, ECO:0000269|PubMed:23818853, ECO:0000269|PubMed:24492532, ECO:0000269|PubMed:24935976, ECO:0000269|PubMed:30872531}.; PTM: [NACHT, LRR and PYD domains-containing protein 1b, N-terminus]: (Microbial infection) Ubiquitinated by S.flexneri IpaH7.8, 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 1b, C-terminus), which polymerizes and forms the Nlrp1b inflammasome. {ECO:0000269|PubMed:30872533}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 17442855; 23152930; 25404286; 25744023; 25964492; 26045162; 28808162; 29571734; 31100244; 31554824; 32421904; 34920732; |
| Motif | |
| Gene Encoded By | |
| Mass | 140,688 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |