Q2LKW6
uniprot
Q2LKW6
canonical
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:30872531, PubMed:31383852). 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:30872531, PubMed:31383852, PubMed:31525884). 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:23230290, PubMed:24935976). 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}.
uniprot
proteins
amino_acid_sequence
MEESPPKQKSNTKVAQHEGQQDLNTTRHMNVELKHRPKLERHLKLGMIPVVYMKQGEEILYPAQSLREENLIQNFTSLLLLQKLCPKDPENMIRKSWASCVPEEGGHMINIQDLFGPNIGTQKEPQLVIIEGAAGIGKSTLARLVKRAWKEGQLYRDHFQHVFFFSCRELAQCKKLSLAELIAQGQEVPTAPINQILSHPEKLLFILDGIDEPAWVLADQNPELCLHWSQRQPVHTLLGSLLGKSILPEAFFLLTTRTTALQKFIPSLPMPCQVEVLGFSGIERENYFYKYFANQRHAITAFMMVESNPVLLTLCEVPWVCWLVCTCLKKQMEQGRVLSLKSQTTTALCLKYLSLTIPDKHRRTQVKALCSLAAEGIWKRRTLFSESDLCKQGLDEDAVATFLKTGVLQKQASSLSYSFAHLCLQEFFAAISCILEDSEERHGNMEMDRIVETLVERYGRQNLFEAPTVRFLFGLLGKEGVKGMEKLFSCSLHGKTNLKLLWHILVKSQPHQPPCLGLLHCLYENQDMELLTHVMHDLQGTIVPGPNDTAHTVLQTNVKHLVVQTDMELMVATFCIQFYCHVRTLQLNMEKQQGYALISPRMVLYRWTPITNASWEILFYNLKFTRNLEGLDLSGNSLRYSVVQSLCNTLRYPGCQLKTLWLVKCGLTSRYCSLLASVLSAHSSLTELYLQLNDLGDDGVRMLCEGLRNPVCNLSILWLDLSSLSAQVITELRTLEEKNPKLYIRSIWMPHMMVPTENMDEEAILTTLKQQRQESGDKPMEILGTEEDFWGPTGPVATELVDRVRNLYRMPQMMVPTENMDEEDILTSFKQQRQQSGANPMEILGTEEDFWGPIGPVATEVVYRERNLYRVQLPMAGSYHCPSTRLHFVVTRAVTIEIEFCAWSQFLDKTPLQQSHMVVGPLFDIKAEQGAVTAVYLPHFVSLKDTKASTFDFKVAHFQEHGMVLETPDRVKPGYTVLKNPSFSPMGVVLRIIPAARHFIPITSITLIYYRVNQEEVTLHLYLVPNDCTIQKAIDDEEMKFQFVRINKPPPVDNLFIGSRYIVSGSENLEITPKELELCYRSSKEFQLFSEIYVGNMGSEIKLQIKNKKHMKLIWEALLKPGDLRPALPRIAQALKDAPSLLHFMDQHREQLVARVTSVDPLLDKLHGLVLNEESYEAVRAENTNQDKMRKLFNLSRSWSRACKDLFYQALKETHPHLVMDLLEKSGGVSLGS
uniprot
proteins
ec_number
3.4.-.-
uniprot
proteins
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:30872531, PubMed:30872533, PubMed:31268597). 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:30872531, PubMed:30872533, PubMed:31268597). 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:30872531, PubMed:30872533, PubMed:31268597). In the absence of GSDMD expression, the Nlrp1b inflammasome is able to recruit and activate CASP8, leading to activation of gasdermin-E (GSDME) (By similarity). 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:0000250|UniProtKB:Q9C000, 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:30872531, PubMed:30872533). 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:30872531, PubMed:30872533). {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:30872531, PubMed:30872533). 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:30872531, PubMed:30872533). 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:30872531, PubMed:30872533, PubMed:31268597). {ECO:0000269|PubMed:30872531, ECO:0000269|PubMed:30872533, ECO:0000269|PubMed:31268597}.
uniprot
proteins
mass_dalton
140688
uniprot
proteins
mutagenesis
MUTAGEN 1..50; /note="Missing: Low spontaneous IL1B release and loss of activation by LT. Increased IL1B release in response to metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 1..44; /note="Missing: Low spontaneous IL1B release and loss of activation by LT. No effect on activation by metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 1..40; /note="Missing: No effect on IL1B release."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 34..36; /note="KHR->AAA: No effect on cleavage by LT, nor on IL1B processing. No effect on cleavage by LT, nor on IL1B processing; when associated with 38-A-A-39."; /evidence="ECO:0000269|PubMed:23818853"; MUTAGEN 37..39; /note="PKL->QAQ: No effect on cleavage by LT."; /evidence="ECO:0000269|PubMed:23818853"; MUTAGEN 38..39; /note="KL->AA: No effect on cleavage by LT, nor on IL1B processing."; /evidence="ECO:0000269|PubMed:23818853"; MUTAGEN 43; /note="L->Q: Loss of cleavage by LT and of LT-induced IL1B processing and suppression of LT-induced pyroptosis in macrophages, no effect on IL1B release in response to metabolic inhibitors; when associated with A-44 and Q-45."; /evidence="ECO:0000269|PubMed:23818853, ECO:0000269|PubMed:24935976"; MUTAGEN 44; /note="K->A: Partial loss of cleavage by LT and of LT-induced IL1B processing. Loss of cleavage by LT and of LT-induced IL1B processing; when associated with Q-43 and Q-45. No effect on IL1B release in response to metabolic inhibitors; when associated with Q-43 and Q-45."; /evidence="ECO:0000269|PubMed:23818853, ECO:0000269|PubMed:24935976"; MUTAGEN 45; /note="L->Q: Loss of cleavage by LT and of LT-induced IL1B processing. Loss of cleavage by LT and of LT-induced IL1B processing; when associated with Q-43 and A-44. No effect on IL1B release in response to metabolic inhibitors; when associated with Q-43 and A-44."; /evidence="ECO:0000269|PubMed:23818853, ECO:0000269|PubMed:24935976"; MUTAGEN 137..139; /note="GKS->AAA: Constitutive IL1B release."; /evidence="ECO:0000269|PubMed:23230290"; MUTAGEN 626..719; /note="Missing: Constitutive IL1B processing."; /evidence="ECO:0000269|PubMed:23818853"; MUTAGEN 629; /note="E->A: Increased IL1B release under basal conditions. No effect on IL1B release in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 632; /note="D->A: Spontaneous IL1B release under basal conditions, loss of response to metabolic inhibitors and to LT; when associated with A-634."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 634; /note="S->A: Spontaneous IL1B release under basal conditions, loss of response to metabolic inhibitors and to LT; when associated with A-632."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 644; /note="Q->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 648; /note="N->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 651; /note="R->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 658; /note="K->A: Spontaneous IL1B release under basal conditions, loss of response to metabolic inhibitors and to LT; when associated with A-659."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 659; /note="T->A: Spontaneous IL1B release under basal conditions, loss of response to metabolic inhibitors and to LT; when associated with A-658."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 661; /note="W->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 663; /note="V->A: Spontaneous IL1B release under basal conditions, loss of response to metabolic inhibitors, no effect on the response to LT; when associated with A-664."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 664; /note="K->A: Spontaneous IL1B release under basal conditions, loss of response to metabolic inhibitors, no effect on the response to LT; when associated with A-663."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 670; /note="R->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 673; /note="S->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 686; /note="T->A: Spontaneous IL1B release under basal conditions, no effect on the response to metabolic inhibitors, partial loss of response to LT; when associated with A-687."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 687; /note="E->A: Spontaneous IL1B release under basal conditions, no effect on the response to metabolic inhibitors, partial loss of response to LT; when associated with A-686."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 689; /note="Y->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 691; /note="Q->A: Low spontaneous IL1B release, no effect on the response to metabolic inhibitors, nor to LT."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 698; /note="D->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors; when associated with A-701 and A-702."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 701; /note="R->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors; when associated with A-698 and A-702."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 702; /note="M->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors; when associated with A-698 and A-701."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 705; /note="E->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 720; /note="D->A: Spontaneous IL1B release under basal conditions, loss of response to metabolic inhibitors and to LT."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 727; /note="Q->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 731; /note="E->A: Increased IL1B release under basal conditions. No effect on IL1B release in response to LT or metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 734; /note="T->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors; when associated with A-738."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 738; /note="K->A: No effect on IL1B release under basal conditions, nor in response to LT or metabolic inhibitors; when associated with A-734."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 744; /note="I->A: Spontaneous IL1B release under basal conditions, loss of response to metabolic inhibitors and to LT; when associated with A-746."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 746; /note="S->A: Spontaneous IL1B release under basal conditions, loss of response to metabolic inhibitors and to LT; when associated with A-744."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 749..809; /note="Missing: No effect on response to LT, attenuated response to metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 810..870; /note="Missing: No effect on response to LT, attenuated response to metabolic inhibitors."; /evidence="ECO:0000269|PubMed:24935976"; MUTAGEN 984; /note="S->A: Loss of autocatalytic cleavage within the FIIND region, abolishing the ability to activate the inflammasome. Abolished interaction with DPP9. No effect on cleavage by LT."; /evidence="ECO:0000269|PubMed:23818853, ECO:0000269|PubMed:29396289, ECO:0000269|PubMed:31525884"; MUTAGEN 988; /note="V->D: Loss of autocatalytic cleavage within the FIIND region and of IL1B release, decrease in CASP1-binding. No effect on homomerization."; /evidence="ECO:0000269|PubMed:22536155"; MUTAGEN 996; /note="A->D: Strong decrease of IL1B release, but no effect on autocatalytic cleavage within the FIIND region."; /evidence="ECO:0000269|PubMed:22536155"; MUTAGEN 1012; /note="V->L: No effect on autocatalytic cleavage within the FIIND region."; /evidence="ECO:0000269|PubMed:22536155"; MUTAGEN 1014; /note="Q->L: No effect on autocatalytic cleavage within the FIIND region."; /evidence="ECO:0000269|PubMed:22536155"; MUTAGEN 1026; /note="N->S: Decrease of IL1B release, but no effect on autocatalytic cleavage within the FIIND region."; /evidence="ECO:0000269|PubMed:22536155"; MUTAGEN 1100..1106; /note="EIKLQIK->AAAAAAA: Loss of homomerization, of autocatalytic cleavage within the FIIND region and of IL1B release. No effect on CASP1-binding."; /evidence="ECO:0000269|PubMed:22536155"; MUTAGEN 1112; /note="K->R: No effect on autocatalytic cleavage within the FIIND region."; /evidence="ECO:0000269|PubMed:22536155
uniprot
proteins
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}.
uniprot
proteins
protein_family
NLRP family
uniprot
proteins
pubmed
16429160
uniprot
proteins
pubmed
19124602
uniprot
proteins
pubmed
19494813
uniprot
proteins
pubmed
19651869
uniprot
proteins
pubmed
19949100
uniprot
proteins
pubmed
21170303
uniprot
proteins
pubmed
22536155
uniprot
proteins
pubmed
22753929
uniprot
proteins
pubmed
22801494
uniprot
proteins
pubmed
23230290
uniprot
proteins
pubmed
23506131
uniprot
proteins
pubmed
23818853
uniprot
proteins
pubmed
24218483
uniprot
proteins
pubmed
24492532
uniprot
proteins
pubmed
24935976
uniprot
proteins
pubmed
29396289
uniprot
proteins
pubmed
30872531
uniprot
proteins
pubmed
30872533
uniprot
proteins
pubmed
31268597
uniprot
proteins
pubmed
31383852
uniprot
proteins
pubmed
31525884
uniprot
proteins
pubmed
32558991
uniprot
proteins
pubmed
33243852
uniprot
proteins
sequence_length
1233
uniprot
proteins
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}.
uniprot
proteins