CARD8_PONAB
ID CARD8_PONAB Reviewed; 427 AA.
AC Q5RAV7;
DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 72.
DE RecName: Full=Caspase recruitment domain-containing protein 8 {ECO:0000305};
DE EC=3.4.-.- {ECO:0000250|UniProtKB:Q9Y2G2};
DE Contains:
DE RecName: Full=Caspase recruitment domain-containing protein 8, C-terminus {ECO:0000305};
DE Short=CARD8-CT {ECO:0000250|UniProtKB:Q9Y2G2};
DE Contains:
DE RecName: Full=Caspase recruitment domain-containing protein 8, N-terminus {ECO:0000305};
DE Short=CARD8-NT {ECO:0000250|UniProtKB:Q9Y2G2};
GN Name=CARD8 {ECO:0000250|UniProtKB:Q9Y2G2};
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Inflammasome sensor, which mediates inflammasome activation
CC in response to various pathogen-associated signals, leading to
CC subsequent pyroptosis of CD4(+) T-cells and macrophages. Inflammasomes
CC are supramolecular complexes that assemble in the cytosol in response
CC to pathogens and other damage-associated signals and play critical
CC roles in innate immunity and inflammation. Acts as a recognition
CC receptor (PRR): recognizes specific pathogens and other damage-
CC associated signals, such as Val-boroPro inhibitor, and mediates CARD8
CC inflammasome activation. In response to pathogen-associated signals,
CC the N-terminal part of CARD8 is degraded by the proteasome, releasing
CC the cleaved C-terminal part of the protein (Caspase recruitment domain-
CC containing protein 8, C-terminus), which polymerizes to initiate the
CC formation of the inflammasome complex: the CARD8 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. Also acts as a negative regulator of the NLRP3
CC inflammasome. May also act as an inhibitor of NF-kappa-B activation.
CC {ECO:0000250|UniProtKB:Q9Y2G2}.
CC -!- FUNCTION: [Caspase recruitment domain-containing protein 8]:
CC Constitutes the precursor of the CARD8 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:Q9Y2G2}.
CC -!- FUNCTION: [Caspase recruitment domain-containing protein 8, N-
CC terminus]: Regulatory part that prevents formation of the CARD8
CC inflammasome: in absence of pathogens and other damage-associated
CC signals, interacts with the C-terminal part of CARD8 (Caspase
CC recruitment domain-containing protein 8, C-terminus), preventing
CC activation of the CARD8 inflammasome. In response to pathogen-
CC associated signals, this part is ubiquitinated by the N-end rule
CC pathway and degraded by the proteasome, releasing the cleaved C-
CC terminal part of the protein, which polymerizes and forms the CARD8
CC inflammasome. {ECO:0000250|UniProtKB:Q9Y2G2}.
CC -!- FUNCTION: [Caspase recruitment domain-containing protein 8, C-
CC terminus]: Constitutes the active part of the CARD8 inflammasome. In
CC absence of pathogens and other damage-associated signals, interacts
CC with the N-terminal part of CARD8 (Caspase recruitment domain-
CC containing protein 8, N-terminus), preventing activation of the CARD8
CC inflammasome. In response to pathogen-associated signals, the N-
CC terminal part of CARD8 is degraded by the proteasome, releasing this
CC form, which polymerizes to form the CARD8 inflammasome complex: the
CC CARD8 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:Q9Y2G2}.
CC -!- ACTIVITY REGULATION: CARD8 inflammasome is inhibited by DPP8 and DPP9,
CC which sequester the C-terminal fragment of CARD8 (Caspase recruitment
CC domain-containing protein 8, C-terminus) in a ternary complex, thereby
CC preventing CARD8 oligomerization and activation. CARD8 inflammasome is
CC activated by Val-boroPro (Talabostat, PT-100), an inhibitor of
CC dipeptidyl peptidases DPP8 and DPP9. Val-boroPro relieves inhibition of
CC DPP8 and/or DPP9 by inducing the proteasome-mediated destruction of the
CC N-terminal part of CARD8, releasing its C-terminal part from
CC autoinhibition. {ECO:0000250|UniProtKB:Q9Y2G2}.
CC -!- SUBUNIT: Interacts with DPP9; leading to inhibit activation of the
CC inflammasome. DPP9 acts via formation of a ternary complex, composed of
CC a DPP9 homodimer, one full-length CARD8 protein, and one cleaved C-
CC terminus of CARD8 (Caspase recruitment domain-containing protein 8, C-
CC terminus). Interacts with DPP8; leading to inhibit activation of the
CC inflammasome, probably via formation of a ternary complex with DPP8.
CC Interacts with NLRP3. Interacts with IKBKG/NEMO. Interacts with DRAL.
CC Binds to caspase-1 (CASP1), CARD16/pseudo-ICE and CARD18/ICEBERG.
CC Interacts with NLRP2 (via NACHT domain).
CC {ECO:0000250|UniProtKB:Q9Y2G2}.
CC -!- SUBUNIT: [Caspase recruitment domain-containing protein 8, N-terminus]:
CC Interacts with the C-terminal part of CARD8 (Caspase recruitment
CC domain-containing protein 8, C-terminus) in absence of pathogens and
CC other damage-associated signals. {ECO:0000250|UniProtKB:Q9Y2G2}.
CC -!- SUBUNIT: [Caspase recruitment domain-containing protein 8, C-terminus]:
CC Interacts with the N-terminal part of CARD8 (Caspase recruitment
CC domain-containing protein 8, N-terminus) in absence of pathogens and
CC other damage-associated signals. Homomultimer; forms the CARD8
CC inflammasome polymeric complex, a filament composed of homopolymers of
CC this form in response to pathogens and other damage-associated signals.
CC The CARD8 inflammasome polymeric complex directly recruits pro-caspase-
CC 1 (proCASP1) independently of PYCARD/ASC. Interacts (via CARD domain)
CC with CASP1 (via CARD domain); leading to CASP1 activation.
CC {ECO:0000250|UniProtKB:Q9Y2G2}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Y2G2}. Nucleus
CC {ECO:0000250|UniProtKB:Q9Y2G2}.
CC -!- SUBCELLULAR LOCATION: [Caspase recruitment domain-containing protein 8,
CC C-terminus]: Inflammasome {ECO:0000250|UniProtKB:Q9Y2G2}.
CC -!- DOMAIN: The disordered region is required for activation of the CARD8
CC inflammasome. {ECO:0000250|UniProtKB:Q9Y2G2}.
CC -!- DOMAIN: [Caspase recruitment domain-containing protein 8, C-terminus]:
CC The C-terminal part of CARD8 oligomerizes to form the core of the CARD8
CC inflammasome filament: in the filament, the CARD domains form a central
CC helical filaments that are promoted by oligomerized, but flexibly
CC linked, UPA regions surrounding the filaments. The UPA region reduces
CC the threshold needed for filament formation and signaling. Directly
CC recruits and polymerizes with the CARD domain of caspase-1 (CASP1)
CC through the favorable side of the growing filament seed.
CC {ECO:0000250|UniProtKB:Q9Y2G2}.
CC -!- PTM: [Caspase recruitment domain-containing protein 8]: Undergoes
CC autocatalytic 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:Q9Y2G2}.
CC -!- PTM: [Caspase recruitment domain-containing protein 8, N-terminus]:
CC Ubiquitinated by the N-end rule pathway in response to pathogens and
CC other damage-associated signals, leading to its degradation by the
CC proteasome and subsequent release of the cleaved C-terminal part of the
CC protein (Caspase recruitment domain-containing protein 8, C-terminus),
CC which polymerizes and forms the CARD8 inflammasome.
CC {ECO:0000250|UniProtKB:Q9Y2G2}.
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DR EMBL; CR858904; CAH91103.1; -; mRNA.
DR RefSeq; NP_001125643.1; NM_001132171.1.
DR AlphaFoldDB; Q5RAV7; -.
DR SMR; Q5RAV7; -.
DR MEROPS; S79.001; -.
DR Ensembl; ENSPPYT00000040900; ENSPPYP00000027845; ENSPPYG00000010191.
DR GeneID; 100172562; -.
DR KEGG; pon:100172562; -.
DR CTD; 22900; -.
DR GeneTree; ENSGT00830000128447; -.
DR InParanoid; Q5RAV7; -.
DR OrthoDB; 559093at2759; -.
DR Proteomes; UP000001595; Chromosome 19.
DR GO; GO:0072559; C:NLRP3 inflammasome complex; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; 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:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR025307; FIIND_dom.
DR Pfam; PF00619; CARD; 1.
DR Pfam; PF13553; FIIND; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR PROSITE; PS50209; CARD; 1.
DR PROSITE; PS51830; FIIND; 1.
PE 2: Evidence at transcript level;
KW Apoptosis; Cytoplasm; Hydrolase; Immunity; Inflammasome;
KW Inflammatory response; Innate immunity; Necrosis; Nucleus; Protease;
KW Reference proteome; Ubl conjugation.
FT CHAIN 1..427
FT /note="Caspase recruitment domain-containing protein 8"
FT /id="PRO_0000144081"
FT CHAIN 1..186
FT /note="Caspase recruitment domain-containing protein 8, N-
FT terminus"
FT /evidence="ECO:0000250|UniProtKB:Q9Y2G2"
FT /id="PRO_0000452849"
FT CHAIN 187..427
FT /note="Caspase recruitment domain-containing protein 8, C-
FT terminus"
FT /evidence="ECO:0000250|UniProtKB:Q9Y2G2"
FT /id="PRO_0000452850"
FT DOMAIN 51..336
FT /note="FIIND"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01174"
FT DOMAIN 336..426
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 1..23
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 51..186
FT /note="ZU5"
FT /evidence="ECO:0000250|UniProtKB:Q9Y2G2"
FT REGION 187..336
FT /note="UPA"
FT /evidence="ECO:0000250|UniProtKB:Q9Y2G2"
FT SITE 186..187
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:Q9Y2G2,
FT ECO:0000255|PROSITE-ProRule:PRU01174"
SQ SEQUENCE 427 AA; 48186 MW; 1AC8A53E4C573FC8 CRC64;
MGIPTSSVSE EQESSEGQDS GDICSEENQI VSSYASKVCF EIEQDYKNRQ FLGPEGNVDV
ELIDKSTNTY SVRFPTAGWY LWPATGLGFL VRDVVTLTIG FGSWNQHLAL DLQHHEQWLV
GGPLFDITAE PEEAVAEIHL PHFISLQAGE VDVSWFLIAH FKNEGMVLEH PARVEPFYAV
LEKPSFSLMG ILLRIASGTR LSIPITSNTL IYYHPHPEDI KFHLYLVPSD ALLTKMIDDE
EDRFCGVRLQ TSPPVEPLNF GARYIVSNSA HLEIIPTELK LSYRSPGEIQ HFSKFYAGQM
KEPIQLEITE KRHETLVWKT VVKPVDIQLG AASAPPAFSG AAFVKENHRQ LQARMGDLKG
VLDDLQDNEV LTENEKELVE QAKTRQSKND TLLTMVEKKG DRALELLFRS ISERDPYLVS
YLRQQSL
