NL1B3_MOUSE
ID NL1B3_MOUSE Reviewed; 1172 AA.
AC Q2LKV5;
DT 09-DEC-2015, integrated into UniProtKB/Swiss-Prot.
DT 21-FEB-2006, sequence version 1.
DT 03-AUG-2022, entry version 98.
DE RecName: Full=NACHT, LRR and PYD domains-containing protein 1b allele 3 {ECO:0000303|PubMed:16429160};
GN Name=Nlrp1b {ECO:0000303|PubMed:19651869};
GN Synonyms=Nalp1b {ECO:0000303|PubMed:16429160};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RC STRAIN=AKR/J, NOD/LtJ, and SJL/J;
RX PubMed=16429160; DOI=10.1038/ng1724;
RA Boyden E.D., Dietrich W.F.;
RT "Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin.";
RL Nat. Genet. 38:240-244(2006).
RN [2]
RP FUNCTION, ACTIVITY REGULATION, AND LACK OF RESPONSE TO BACILLUS ANTHRACIS
RP LETHAL TOXIN.
RX PubMed=19651869; DOI=10.1128/iai.00276-09;
RA Liao K.C., Mogridge J.;
RT "Expression of Nlrp1b inflammasome components in human fibroblasts confers
RT susceptibility to anthrax lethal toxin.";
RL Infect. Immun. 77:4455-4462(2009).
RN [3]
RP TISSUE SPECIFICITY.
RX PubMed=23506131; DOI=10.1186/1471-2164-14-188;
RA Sastalla I., Crown D., Masters S.L., McKenzie A., Leppla S.H., Moayeri M.;
RT "Transcriptional analysis of the three Nlrp1 paralogs in mice.";
RL BMC Genomics 14:188-188(2013).
RN [4]
RP FUNCTION, AND MUTAGENESIS OF ASP-927; ASP-935 AND SER-965.
RX PubMed=22536155; DOI=10.1371/journal.ppat.1002659;
RA Frew B.C., Joag V.R., Mogridge J.;
RT "Proteolytic processing of Nlrp1b is required for inflammasome activity.";
RL PLoS Pathog. 8:E1002659-E1002659(2012).
RN [5]
RP LACK OF RESPONSE TO ANTHRAX LETHAL TOXIN AND METABOLIC INHIBITORS, ACTIVITY
RP REGULATION, FUNCTION, AND MUTAGENESIS OF ASP-927.
RX PubMed=23230290; DOI=10.1128/iai.01003-12;
RA Liao K.C., Mogridge J.;
RT "Activation of the Nlrp1b inflammasome by reduction of cytosolic ATP.";
RL Infect. Immun. 81:570-579(2013).
RN [6]
RP FUNCTION, ACTIVITY REGULATION, AND LACK OF PROTEOLYTIC CLEAVAGE.
RX PubMed=31383852; DOI=10.1038/s41419-019-1817-5;
RA Gai K., Okondo M.C., Rao S.D., Chui A.J., Ball D.P., Johnson D.C.,
RA Bachovchin D.A.;
RT "DPP8/9 inhibitors are universal activators of functional NLRP1 alleles.";
RL Cell Death Dis. 10:587-587(2019).
RN [7]
RP REVIEW.
RX PubMed=32558991; DOI=10.1111/imr.12884;
RA Taabazuing C.Y., Griswold A.R., Bachovchin D.A.;
RT "The NLRP1 and CARD8 inflammasomes.";
RL Immunol. Rev. 297:13-25(2020).
CC -!- FUNCTION: May act as the sensor component of the Nlrp1b inflammasome,
CC which mediates inflammasome activation in response to various pathogen-
CC associated signals, leading to subsequent pyroptosis (By similarity).
CC Inflammasomes are supramolecular complexes that assemble in the cytosol
CC in response to pathogens and other damage-associated signals and play
CC critical roles in innate immunity and inflammation (By similarity). May
CC act as a recognition receptor (PRR), which recognizes specific
CC pathogens and other damage-associated signals and forms an inflammasome
CC complex: the inflammasome directly recruits pro-caspase-1 (proCASP1)
CC independently of PYCARD/ASC and promotes caspase-1 (CASP1) activation,
CC which subsequently cleaves and activates inflammatory cytokines IL1B
CC and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (By.
CC similarity). Contrary to Nlrp1b allele 1, allele 3 is not activated by
CC Bacillus anthracis lethal toxin (PubMed:16429160, PubMed:19651869,
CC PubMed:23230290). The absence of autocatalytic cleavage within the
CC FIIND domain, which regulates activation in other alleles, suggests
CC that allele 3 may be non-functional (PubMed:31383852).
CC {ECO:0000250|UniProtKB:Q2LKW6, ECO:0000269|PubMed:16429160,
CC ECO:0000269|PubMed:19651869, ECO:0000269|PubMed:23230290,
CC ECO:0000269|PubMed:31383852}.
CC -!- ACTIVITY REGULATION: In contrast to allele 1, does not undergo
CC autocatalytic cleavage within the FIIND domain and its mode of
CC activation remains unclear (PubMed:32558991). In contrast to alleles 1
CC and 2, allele 3 is not activated by Val-boroPro (Talabostat, PT-100)
CC (PubMed:31383852). Not activated by cleavage by B.anthracis lethal
CC toxin (LT) endopeptidase (PubMed:16429160, PubMed:23230290,
CC PubMed:31383852). Not activated by metabolic inhibitors, such as 2-
CC deoxy-D-glucose and sodium azide (PubMed:23230290).
CC {ECO:0000269|PubMed:16429160, ECO:0000269|PubMed:23230290,
CC ECO:0000269|PubMed:31383852, ECO:0000303|PubMed:32558991}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q2LKW6}.
CC -!- TISSUE SPECIFICITY: Expressed in macrophages.
CC {ECO:0000269|PubMed:16429160, ECO:0000269|PubMed:23506131}.
CC -!- DOMAIN: The FIIND (domain with function to find) region may be involved
CC in homomerization, but not in CASP1-binding. Contrary to allele 1,
CC allele 3 does not undergo autocatalytic cleavage in this region.
CC {ECO:0000269|PubMed:22536155}.
CC -!- PTM: In contrast to allele 1 and 2, not able to mediate autocatalytic
CC cleavage. {ECO:0000269|PubMed:22536155, ECO:0000269|PubMed:31383852}.
CC -!- POLYMORPHISM: Nlrp1b gene is extremely polymorphic. 5 alleles have been
CC described in 18 inbred strains: 1 (AC Q2LKW6), 2 (AC A1Z198), 3 (this
CC entry), 4 (AC Q2LKV2) and 5 (AC Q0GKD5). These alleles define
CC susceptibility to B.anthracis lethal toxin (LT). Alleles 2 (carried by
CC A/J, C57BL/6J and I/LnJ), 3 (AKR/J, NOD/LtJ and SJL/J) or 4 (DBA/2J,
CC P/J and SM/J) are not activated by LT. Alleles 1 (carried by
CC 129S1/SvImJ, BALB/cJ, C3H/HeJ, CBA/J, FVB/NJ, NON/ShiLtJ, NZO
CC (NZO/HlLtJ) and SWR/J strains) and 5 (CAST/EiJ) confer macrophage
CC susceptibility to LT. In susceptible strains, infection by Bacillus
CC anthracis leads to IL1B release, neutrophil recruitment and macrophage
CC pyroptosis. This early inflammatory response confers increased
CC resistance to infection (PubMed:16429160). The sequence shown in this
CC entry is that of allele 3 (PubMed:16429160).
CC {ECO:0000269|PubMed:16429160, ECO:0000303|PubMed:16429160}.
CC -!- MISCELLANEOUS: Three tandem Nrlp1 paralogs, Nrlp1a, Nrlp1b and Nrlp1c,
CC have been identified. Nlrp1c is predicted to be a pseudogene.
CC {ECO:0000269|PubMed:23506131, ECO:0000305|PubMed:16429160}.
CC -!- MISCELLANEOUS: In macrophages and dendritic cells, NLRP1 inflammasome
CC activation of CASP1 and IL1B maturation can be dampened by direct
CC contact with activated effector and memory T-cells. This effect may be
CC mediated by hexameric TNF ligands, such as CD40LG.
CC {ECO:0000250|UniProtKB:Q2LKW6}.
CC -!- SIMILARITY: Belongs to the NLRP family. {ECO:0000305}.
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DR EMBL; DQ117594; AAZ40520.1; -; mRNA.
DR EMBL; DQ117595; AAZ40521.1; -; mRNA.
DR EMBL; DQ117596; AAZ40522.1; -; mRNA.
DR AlphaFoldDB; Q2LKV5; -.
DR SMR; Q2LKV5; -.
DR ComplexPortal; CPX-4269; NLRP1b inflammasome, allele-3 variant.
DR PRIDE; Q2LKV5; -.
DR MGI; MGI:3582959; Nlrp1b.
DR GO; GO:0005737; C:cytoplasm; IC:ComplexPortal.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0061702; C:inflammasome complex; ISO:MGI.
DR GO; GO:0072558; C:NLRP1 inflammasome complex; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; ISO:MGI.
DR GO; GO:0016887; F:ATP hydrolysis activity; ISO:MGI.
DR GO; GO:0140608; F:cysteine-type endopeptidase activator activity; ISO:MGI.
DR GO; GO:0003690; F:double-stranded DNA binding; ISO:MGI.
DR GO; GO:0003725; F:double-stranded RNA binding; ISO:MGI.
DR GO; GO:0004175; F:endopeptidase activity; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0019904; F:protein domain specific binding; ISO:MGI.
DR GO; GO:0043621; F:protein self-association; ISO:MGI.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:MGI.
DR GO; GO:0140374; P:antiviral innate immune response; ISO:MGI.
DR GO; GO:0051607; P:defense response to virus; ISO:MGI.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0051402; P:neuron apoptotic process; ISO:MGI.
DR GO; GO:1904784; P:NLRP1 inflammasome complex assembly; ISO:MGI.
DR GO; GO:0002221; P:pattern recognition receptor signaling pathway; IC:ComplexPortal.
DR GO; GO:0050729; P:positive regulation of inflammatory response; ISO:MGI.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISO:MGI.
DR GO; GO:0030163; P:protein catabolic process; IMP:MGI.
DR GO; GO:0051260; P:protein homooligomerization; ISO:MGI.
DR GO; GO:0070269; P:pyroptosis; IMP:MGI.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
DR GO; GO:0097264; P:self proteolysis; ISO:MGI.
DR CDD; cd08330; CARD_ASC_NALP1; 1.
DR Gene3D; 1.10.533.10; -; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR Gene3D; 3.80.10.10; -; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR033516; CARD8/ASC/NALP1_CARD.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR025307; FIIND_dom.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR007111; NACHT_NTPase.
DR InterPro; IPR041267; NLRP_HD2.
DR InterPro; IPR041075; NOD2_WH.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF00619; CARD; 1.
DR Pfam; PF13553; FIIND; 1.
DR Pfam; PF05729; NACHT; 1.
DR Pfam; PF17776; NLRC4_HD2; 1.
DR Pfam; PF17779; NOD2_WH; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS50209; CARD; 1.
DR PROSITE; PS51830; FIIND; 1.
DR PROSITE; PS50837; NACHT; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cytoplasm; Immunity; Inflammatory response; Innate immunity;
KW Leucine-rich repeat; Nucleotide-binding; Repeat.
FT CHAIN 1..1172
FT /note="NACHT, LRR and PYD domains-containing protein 1b
FT allele 3"
FT /id="PRO_0000435105"
FT DOMAIN 126..435
FT /note="NACHT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT REPEAT 627..647
FT /note="LRR 1"
FT REPEAT 684..704
FT /note="LRR 2"
FT DOMAIN 789..1072
FT /note="FIIND"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01174"
FT DOMAIN 1082..1165
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 789..922
FT /note="ZU5"
FT /evidence="ECO:0000250|UniProtKB:Q9C000"
FT REGION 923..1072
FT /note="UPA"
FT /evidence="ECO:0000250|UniProtKB:Q9C000"
FT COMPBIAS 8..22
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 132..139
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT SITE 922..923
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01174"
FT MUTAGEN 927
FT /note="D->V: Restores autocatalytic cleavage, as observed
FT in allele 1, but not response to anthrax lethal toxin (LT),
FT nor to metabolic inhibitors. Restores autocatalytic
FT cleavage and IL1B release in response to LT; when
FT associated with A-935 and N-965."
FT /evidence="ECO:0000269|PubMed:22536155,
FT ECO:0000269|PubMed:23230290"
FT MUTAGEN 935
FT /note="D->A: No effect; when associated with N-965.
FT Restores autocatalytic cleavage and IL1B release in
FT response to anthrax lethal toxin; when associated with V-
FT 927 and N-965."
FT /evidence="ECO:0000269|PubMed:22536155"
FT MUTAGEN 965
FT /note="S->N: Restores autocatalytic cleavage, as observed
FT in allele 1, and produces constitutive IL1B release; when
FT associated with V-927 and A-935."
FT /evidence="ECO:0000269|PubMed:22536155"
SQ SEQUENCE 1172 AA; 133631 MW; 8588C509568BE397 CRC64;
MEESPPKQKS NTKVAQHEGQ QDLNTTRHMN VELKHRPKLE RHLKLGMIPV VYMKQREEIL
YPAQSLKEEN LIQNFTSLPL LQKLYPKDPE NMVRKSWASC IPEEGGHMIN IQDLFGPNIG
TQKEPQLVII EGAAGIGKST LARLVKRAWK EGQLYRDHFQ HVFFFSCREL AQCKKLSLAE
LIAQGQEVPT APINQILSHP EKLLFILDGI DEPAWVLADQ NPELCLHWSQ RQPVHTLLGS
LLGKSILPEA FFLLTTRTTA LQKFIPSLPM PCQVEVLGFS GIERENYFYK YFANQRHAIT
AFMMVESNPV LLTLCEVPWV CWLVCTCLKK QMEQGRVLSL KSQTTTALCL KYPSLTIPDK
HRRTQVKALC SLAAEGIWKR RTLFSESDLC KQGLDEDAVA TFLKTGVLQK QASSLSYSFA
HLCLQEFFAA ISCILEDSEE RHGNMEMDRI VETLVERYGR QNLFEAPTVR FLFGLLGKEG
VKGMEKLFSC SLHGKTKLKL LWHILGKSQP HQPSCLGLLH CLYENQDMEL LTHVMHDLQG
TIVPGPNDIA HTVLQTNVKQ LVVQTDMELM VATFCIQFYC HVRTLQLNME KQQGYALTSP
RMVLYRWTPI TNASWEILFY NLKFTRNLEG LDLSGNSLRY SVVQSLCNTL RYPGCQLKTL
WLVKCGLTSR YCSLLASVLS AHSSLTELYL QLNDLGDDGV RMLCEGLRNP VCNLSILWLD
LSSLSAQVIT ELRTLEEKNP KLYIRSIWMP HMMVPTENMD EEAILTTFKQ QRQESGDKPM
EILGTEEDFW GPTGPVATEL VDRVRNLYRV QLPMAGSYHC PSTGLHFVVT RAVTIEIEFC
AWSQFLDKTP LQQSHMVVGP LFDIKAEQGA VTAVYLPHFV SLKDTEASTF DFKVAHFQEH
GIVLETPDRV KPGYTVLKNP SFSPMGDVLR IIPADRHFIP ITSITLIYYR LNLEEVTLHL
YLVPSDCTIQ KAIDDEEMKF QFVRINKPPP VDNLFIGSRY IVSGSENLEI TPKELELCYR
SSKEFQLFSE IYVGNMGSEI KLQIKNKKHM RLIWEALLKP GDLRPALPRI AQALKDAPSL
LHFMDQHREQ LVARVTSVDP LLDKLHGLVL NEESYEAVRA ENTNQDKMRK LFNLSRSWSR
ACKDLFYQAL KETHPHLVMD LLEKSGGVSL GS
