NL1A3_RAT
ID NL1A3_RAT Reviewed; 1218 AA.
AC D9I2H0;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 05-OCT-2010, sequence version 1.
DT 03-AUG-2022, entry version 53.
DE RecName: Full=NACHT, LRR and PYD domains-containing protein 1a allele 3 {ECO:0000305};
DE EC=3.4.-.- {ECO:0000250|UniProtKB:Q9C000};
DE Contains:
DE RecName: Full=NACHT, LRR and PYD domains-containing protein 1a, C-terminus {ECO:0000305};
DE Short=Nlrp1a-CT {ECO:0000250|UniProtKB:Q9C000};
DE Contains:
DE RecName: Full=NACHT, LRR and PYD domains-containing protein 1a, N-terminus {ECO:0000305};
DE Short=Nlrp1a-NT {ECO:0000250|UniProtKB:Q9C000};
GN Name=Nlrp1a {ECO:0000250|UniProtKB:D9I2F9};
GN Synonyms=Nlrp1 {ECO:0000303|PubMed:20502689};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ACTIVITY REGULATION.
RC STRAIN=Z {ECO:0000312|EMBL:ADI96236.1};
RX PubMed=20502689; DOI=10.1371/journal.ppat.1000906;
RA Newman Z.L., Printz M.P., Liu S., Crown D., Breen L., Miller-Randolph S.,
RA Flodman P., Leppla S.H., Moayeri M.;
RT "Susceptibility to anthrax lethal toxin-induced rat death is controlled by
RT a single chromosome 10 locus that includes rNlrp1.";
RL PLoS Pathog. 6:e1000906-e1000906(2010).
RN [2]
RP FUNCTION, AND ACTIVITY REGULATION.
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 [3]
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: Acts as the sensor component of the Nlrp1a 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).
CC Acts as a recognition receptor (PRR): recognizes specific pathogens and
CC other damage-associated signals, such as Val-boroPro inhibitor, and
CC mediates the formation of the inflammasome polymeric complex
CC (PubMed:31383852). In response to pathogen-associated signals, the N-
CC terminal part of Nlrp1a is degraded by the proteasome, releasing the
CC cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-
CC containing protein 1a, C-terminus), which polymerizes to initiate the
CC formation of the inflammasome complex: the inflammasome directly
CC recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC and
CC promotes caspase-1 (CASP1) activation, which subsequently cleaves and
CC activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD),
CC leading to pyroptosis (By similarity). {ECO:0000250|UniProtKB:Q2LKU9,
CC ECO:0000250|UniProtKB:Q2LKW6, ECO:0000250|UniProtKB:Q9C000,
CC ECO:0000269|PubMed:31383852}.
CC -!- FUNCTION: [NACHT, LRR and PYD domains-containing protein 1a allele 3]:
CC Constitutes the precursor of the Nlrp1a inflammasome, which mediates
CC autoproteolytic processing within the FIIND domain to generate the N-
CC terminal and C-terminal parts, which are associated non-covalently in
CC absence of pathogens and other damage-associated signals.
CC {ECO:0000250|UniProtKB:Q9C000}.
CC -!- FUNCTION: [NACHT, LRR and PYD domains-containing protein 1a, N-
CC terminus]: Regulatory part that prevents formation of the Nlrp1a
CC inflammasome: in absence of pathogens and other damage-associated
CC signals, interacts with the C-terminal part of Nlrp1a (NACHT, LRR and
CC PYD domains-containing protein 1a, C-terminus), preventing activation
CC of the Nlrp1a inflammasome. In response to pathogen-associated signals,
CC this part is ubiquitinated by the N-end rule pathway and degraded by
CC the proteasome, releasing the cleaved C-terminal part of the protein,
CC which polymerizes and forms the Nlrp1a inflammasome.
CC {ECO:0000250|UniProtKB:Q9C000}.
CC -!- FUNCTION: [NACHT, LRR and PYD domains-containing protein 1a, C-
CC terminus]: Constitutes the active part of the Nlrp1a inflammasome. In
CC absence of pathogens and other damage-associated signals, interacts
CC with the N-terminal part of Nlrp1a (NACHT, LRR and PYD domains-
CC containing protein 1a, N-terminus), preventing activation of the Nlrp1a
CC inflammasome. In response to pathogen-associated signals, the N-
CC terminal part of Nlrp1a is degraded by the proteasome, releasing this
CC form, which polymerizes to form the Nlrp1a inflammasome complex: the
CC Nlrp1a inflammasome complex then directly recruits pro-caspase-1
CC (proCASP1) and promotes caspase-1 (CASP1) activation, leading to
CC gasdermin-D (GSDMD) cleavage and subsequent pyroptosis.
CC {ECO:0000250|UniProtKB:Q9C000}.
CC -!- ACTIVITY REGULATION: Activated by pathogens and other damage-associated
CC signals: activation promotes ubiquitination and degradation of the N-
CC terminal part, releasing the cleaved C-terminal part of the protein
CC (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), which
CC polymerizes and forms the Nlrp1a inflammasome (By similarity). Nlrp1a
CC inflammasome is inhibited by DPP8 and DPP9, which sequester the C-
CC terminal fragment of Nlrp1a (NACHT, LRR and PYD domains-containing
CC protein 1a, C-terminus) in a ternary complex, thereby preventing Nlrp1a
CC oligomerization and activation (By similarity). Nlrp1a inflammasome is
CC strongly activated by Val-boroPro (Talabostat, PT-100), an inhibitor of
CC dipeptidyl peptidases DPP8 and DPP9 (PubMed:31383852). Val-boroPro
CC relieves inhibition of DPP8 and/or DPP9 by promoting disruption of the
CC ternary complex, releasing its C-terminal part from autoinhibition (By
CC similarity). Not activated by cleavage by B.anthracis lethal toxin (LT)
CC endopeptidase (PubMed:20502689). {ECO:0000250|UniProtKB:D9I2F9,
CC ECO:0000250|UniProtKB:Q2LKW6, ECO:0000269|PubMed:20502689,
CC ECO:0000269|PubMed:31383852}.
CC -!- SUBUNIT: Interacts (via LRR repeats) with BCL2 and BCL2L1 (via the loop
CC between motifs BH4 and BH3). Interacts with NOD2; this interaction is
CC enhanced in the presence of muramyl dipeptide (MDP) and increases IL1B
CC release. Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2
CC activity, is accompanied by EIF2AK2 autophosphorylation and promotes
CC inflammasome assembly in response to danger-associated signals.
CC Interacts with MEFV; this interaction targets Nlrp1a to degradation by
CC autophagy, hence preventing excessive IL1B- and IL18-mediated
CC inflammation. Interacts with DPP9; leading to inhibit activation of the
CC inflammasome (By similarity). DPP9 acts via formation of a ternary
CC complex, composed of a DPP9 homodimer, one full-length NLRP1 protein,
CC and one cleaved C-terminus of Nlrp1a (NACHT, LRR and PYD domains-
CC containing protein 1a, C-terminus) (By similarity). Interacts with
CC DPP8; leading to inhibit activation of the inflammasome, probably via
CC formation of a ternary complex with DPP8 (By similarity).
CC {ECO:0000250|UniProtKB:D9I2F9, ECO:0000250|UniProtKB:Q9C000}.
CC -!- SUBUNIT: [NACHT, LRR and PYD domains-containing protein 1a, N-
CC terminus]: Interacts with the C-terminal part of Nlrp1a (NACHT, LRR and
CC PYD domains-containing protein 1a, C-terminus) in absence of pathogens
CC and other damage-associated signals. {ECO:0000250|UniProtKB:Q9C000}.
CC -!- SUBUNIT: [NACHT, LRR and PYD domains-containing protein 1a, C-
CC terminus]: Interacts with the N-terminal part of Nlrp1a (NACHT, LRR and
CC PYD domains-containing protein 1a, N-terminus) in absence of pathogens
CC and other damage-associated signals (By similarity). Homomultimer;
CC forms the Nlrp1a inflammasome polymeric complex, a filament composed of
CC homopolymers of this form in response to pathogens and other damage-
CC associated signals (By similarity). The Nlrp1a inflammasome polymeric
CC complex directly recruits pro-caspase-1 (proCASP1) independently of
CC PYCARD/ASC (By similarity). Interacts (via CARD domain) with CASP1 (via
CC CARD domain); leading to CASP1 activation (By similarity).
CC {ECO:0000250|UniProtKB:Q9C000}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q9C000}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q9C000}. Nucleus {ECO:0000250|UniProtKB:Q9C000}.
CC -!- SUBCELLULAR LOCATION: [NACHT, LRR and PYD domains-containing protein
CC 1a, C-terminus]: Inflammasome {ECO:0000250|UniProtKB:Q9C000}.
CC -!- DOMAIN: The leucine-rich repeat (LRR) domain may be involved in
CC autoinhibition in the absence of activating signal, possibly through
CC intramolecular interaction with the NACHT domain.
CC {ECO:0000250|UniProtKB:Q2LKW6}.
CC -!- DOMAIN: The FIIND (domain with function to find) region is involved in
CC homomerization, but not in CASP1-binding. Autocatalytic cleavage in
CC this region occurs constitutively, prior to activation signals, and is
CC required for inflammasome activity (IL1B release), possibly by
CC facilitating CASP1 binding. Both N- and C-terminal fragments remain
CC associated. {ECO:0000250|UniProtKB:Q2LKW6}.
CC -!- DOMAIN: [NACHT, LRR and PYD domains-containing protein 1a, C-terminus]:
CC The C-terminal part of Nlrp1a oligomerizes to form the core of the
CC Nlrp1a inflammasome filament: in the filament, the CARD domains form a
CC central helical filaments that are promoted by oligomerized, but
CC flexibly linked, UPA regions surrounding the filaments. The UPA region
CC reduces the threshold needed for filament formation and signaling.
CC {ECO:0000250|UniProtKB:Q9C000}.
CC -!- PTM: [NACHT, LRR and PYD domains-containing protein 1a allele 3]:
CC Autocatalytically cleaved. Autocatalytic cleavage in FIIND region
CC occurs constitutively, prior to activation signals, and is required for
CC inflammasome activity (IL1B release), possibly by facilitating CASP1
CC binding. Both N- and C-terminal parts remain associated non-covalently.
CC {ECO:0000250|UniProtKB:Q9C000}.
CC -!- PTM: [NACHT, LRR and PYD domains-containing protein 1a, N-terminus]:
CC Ubiquitinated in response to pathogen-associated signals, leading to
CC its degradation by the proteasome and subsequent release of the cleaved
CC C-terminal part of the protein (NACHT, LRR and PYD domains-containing
CC protein 1a, C-terminus), which polymerizes and forms the Nlrp1a
CC inflammasome. {ECO:0000250|UniProtKB:Q9C000}.
CC -!- POLYMORPHISM: Nlrp1a gene is extremely polymorphic. 5 alleles have been
CC described: 1 (AC D9I2F9), 2 (AC D9I2G3), 3 (this entry), 4 (AC D9I2G1)
CC and 5 (AC D9I2G4). {ECO:0000269|PubMed:20502689}.
CC -!- SIMILARITY: Belongs to the NLRP family. {ECO:0000305}.
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DR EMBL; HM060639; ADI96236.1; -; mRNA.
DR AlphaFoldDB; D9I2H0; -.
DR SMR; D9I2H0; -.
DR GO; GO:0061702; C:inflammasome complex; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0012501; P:programmed cell death; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
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; IPR001611; Leu-rich_rpt.
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; PF13516; LRR_6; 2.
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 2: Evidence at transcript level;
KW ATP-binding; Cytoplasm; Hydrolase; Immunity; Inflammasome;
KW Inflammatory response; Innate immunity; Leucine-rich repeat; Necrosis;
KW Nucleotide-binding; Nucleus; Protease; Repeat; Ubl conjugation.
FT CHAIN 1..1218
FT /note="NACHT, LRR and PYD domains-containing protein 1a
FT allele 3"
FT /id="PRO_0000452884"
FT CHAIN 1..968
FT /note="NACHT, LRR and PYD domains-containing protein 1a, N-
FT terminus"
FT /evidence="ECO:0000250|UniProtKB:Q9C000"
FT /id="PRO_0000452885"
FT CHAIN 969..1218
FT /note="NACHT, LRR and PYD domains-containing protein 1a, C-
FT terminus"
FT /evidence="ECO:0000250|UniProtKB:Q9C000"
FT /id="PRO_0000452886"
FT DOMAIN 175..484
FT /note="NACHT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT REPEAT 343..364
FT /note="LRR 1"
FT /evidence="ECO:0000255"
FT REPEAT 673..693
FT /note="LRR 2"
FT /evidence="ECO:0000255"
FT REPEAT 730..750
FT /note="LRR 3"
FT /evidence="ECO:0000255"
FT DOMAIN 835..1118
FT /note="FIIND"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01174"
FT DOMAIN 1122..1211
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 1..44
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 71..91
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 799..842
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 835..968
FT /note="ZU5"
FT /evidence="ECO:0000250|UniProtKB:Q9C000"
FT REGION 969..1118
FT /note="UPA"
FT /evidence="ECO:0000250|UniProtKB:Q9C000"
FT COMPBIAS 1..27
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 799..825
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 181..188
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT SITE 942
FT /note="Trigger for autolytic processing"
FT /evidence="ECO:0000250|UniProtKB:Q9C000"
FT SITE 968..969
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01174"
SQ SEQUENCE 1218 AA; 138235 MW; 1C054FEFACF6708B CRC64;
MGESQSKQES NTRVAQHGSQ QDVDPTFQTK RALERERSSP QVEQSFLGQL QSLLGWSSTS
KDVPLSQLIR EMDHESRRHS HQSKKKLDRS EHISEGTIPE IYEKRKETIS HTQSMEQKYL
FQNFTKLLLL QKCCPGGSEK LVRESWHPCV PEEGGHMIEI QDLFDPNLDT EKKPQLVIIE
GAAGIGKSTL ARQVKRAWDE GQLYRDRFQH VFFFSCRELA QCKQLSLAEL IAQGQEVPTA
PTRQILSRPE KLLFILDGID EPAWVLEDQN PELCVHWSQA QPVHTLLGSL LGKSILPEAS
LMLTARTTAL QKLVPSLGQP HRVEVLGFSE FERKDYFYKY FAKERNTIID FNLIGSIPVL
LTLCEVPWVC WLLCTCLEKQ MQQGEVLSLT SQTTTALCLK YLSLTIPGQH LSTQLRTLCS
LAAEGICQRR TLFSKSDLCK QGLAEDAIAT FLKIGVLQRQ PSSLSYSFAH LCLQEFFAAM
SYILEDSEEA HGDMGNDRTV ETLVERYGRQ NLFEAPTVRF LLGLLNTREM REMENIFACK
FPWETKLKLL QSIIGEPFCQ PCHLGLFHCL YENQEEELLT ETMLCFPLTA SGPNHMEATV
FQTNVKRLVI QTDMELMVVT FCITFSHVRS LRLKGKGQQE YKLTAPAMVL YRWTPISEAS
WKVLFSNLKC TRNLEELDLS GNPLSYSAVR SLCTALRQPG CRLKTLWLVD CGLTSRCCSF
LASMLSAHSR LAELDLRLND LGDNGVRQLC EGLRNPACNL SILRLDQASL SEQVITELRA
LETKNPKLFI SSTWMSHMTM PTENTDGEES LTSSKQQQQQ SGDKHMEPLG TDDDFWGPSG
PVSTEVVDRE RNLYRVRLPM AGSYHCPSTG LHFVVTRAVT IEIGFCAWSQ FLHETPLQHS
HMVAGPLFDI KAEHGAVTAV CLPHFVSLQE GKVDSSLFHV AHFQDHGMVL ETPARVEPHF
AVLENPSFSP MGVLLRMIPA VGHFIPITSI TLIYYRLYLE DITFHLYLVP NDCTIRKAID
EEELKFQFVR INKPPPVDAL YVGSRYIVSS SKEVEILPKE LELCYRSPRE SQLFSEIYVG
NIGSGINLQL TDKKYMNLIW EALLKPGDLR PALPRMASAP KDAPALLHFV DQHREQLVAR
VTSVDPLLDK LHGLVLSEED YETVRAEATN QDKMRKLFRG SRSWSWDCKD HFYQALKETH
PHLIMDLLEK SGGVSVRL
