UniProt functional annotation for P29466



	UniProt functional annotation for P29466

UniProt code: P29466.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Thiol protease involved in a variety of inflammatory processes by proteolytically cleaving other proteins, such as the precursors of the inflammatory cytokines interleukin-1 beta (IL1B) and interleukin 18 (IL18) as well as the pyroptosis inducer Gasdermin-D (GSDMD), into active mature peptides (PubMed:15326478, PubMed:1574116, PubMed:7876192, PubMed:15498465, PubMed:26375003, PubMed:32051255). Plays a key role in cell immunity as an inflammatory response initiator: once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage of the two inflammatory cytokines IL1B and IL18, releasing the mature cytokines which are involved in a variety of inflammatory processes (PubMed:1574116, PubMed:7876192, PubMed:15498465, PubMed:15326478, PubMed:32051255). Cleaves a tetrapeptide after an Asp residue at position P1 (PubMed:1574116, PubMed:7876192, PubMed:15498465). Also initiates pyroptosis, a programmed lytic cell death pathway, through cleavage of GSDMD (PubMed:26375003). In contrast to cleavage of interleukins IL1B and IL1B, recognition and cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP1 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32051255, PubMed:32109412, PubMed:32553275). Upon inflammasome activation, during DNA virus infection but not RNA virus challenge, controls antiviral immunity through the cleavage of CGAS, rendering it inactive (PubMed:28314590). In apoptotic cells, cleaves SPHK2 which is released from cells and remains enzymatically active extracellularly (PubMed:20197547). {ECO:0000269|PubMed:15326478, ECO:0000269|PubMed:15498465, ECO:0000269|PubMed:1574116, ECO:0000269|PubMed:20197547, ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:32051255, ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:32553275, ECO:0000269|PubMed:7876192}.

Function: [Isoform Delta]: Apoptosis inactive. {ECO:0000269|PubMed:7876192}.

Function: [Isoform Epsilon]: Apoptosis inactive. {ECO:0000269|PubMed:7876192}.

Catalytic activity: Reaction=Strict requirement for an Asp residue at position P1 and has a preferred cleavage sequence of Tyr-Val-Ala-Asp-|-.; EC=3.4.22.36; Evidence={ECO:0000269|PubMed:1574116};

Activity regulation: (Microbial infection) Specifically inhibited by the cowpox virus Crma protein. {ECO:0000269|PubMed:1339309}.

Subunit: Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-1 subunit p20) and a 10 kDa (Caspase-1 subunit p10) subunit (PubMed:8044845, PubMed:9987822, PubMed:32109412, PubMed:32553275). May be a component of the inflammasome, a protein complex which also includes PYCARD, CARD8 and NLRP2 and whose function would be the activation of proinflammatory caspases (PubMed:15030775, PubMed:33420033). Interacts with CARD8; interacts with the released C-terminus of CARD8 which forms an inflammasome and directly activates CASP1 to promote pyroptosis (PubMed:32051255). Both the p10 and p20 subunits interact with MEFV (PubMed:16785446). Interacts with CARD17/INCA and CARD18 (PubMed:15383541, PubMed:11051551). Interacts with SERPINB1; this interaction regulates CASP1 activity (PubMed:30692621). {ECO:0000269|PubMed:11051551, ECO:0000269|PubMed:15030775, ECO:0000269|PubMed:15383541, ECO:0000269|PubMed:16785446, ECO:0000269|PubMed:30692621, ECO:0000269|PubMed:32051255, ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:32553275, ECO:0000269|PubMed:8044845, ECO:0000269|PubMed:9987822}.

Subunit: [Caspase-1 subunit p20]: Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-1 subunit p20) and a 10 kDa (Caspase-1 subunit p10) subunit (PubMed:8044845, PubMed:32109412, PubMed:32553275). Can form a heterodimer with isoform epsilon which then has an inhibitory effect (PubMed:7876192). {ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:32553275, ECO:0000269|PubMed:7876192, ECO:0000269|PubMed:8044845}.

Subunit: [Caspase-1 subunit p10]: Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-1 subunit p20) and a 10 kDa (Caspase-1 subunit p10) subunit. {ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:32553275, ECO:0000269|PubMed:8044845}.

Subunit: [Isoform Epsilon]: Can form a heterodimer with Caspase-1 subunit p20 which then has an inhibitory effect. {ECO:0000269|PubMed:7876192}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:20197547}. Cell membrane {ECO:0000269|PubMed:20197547}.

Tissue specificity: Expressed in larger amounts in spleen and lung. Detected in liver, heart, small intestine, colon, thymus, prostate, skeletal muscle, peripheral blood leukocytes, kidney and testis. No expression in the brain. {ECO:0000269|PubMed:15498465}.

Induction: Transcription and translation induced by M.tuberculosis and a number of different M.tuberculosis components; EsxA is the most potent activator tested (at protein level) (PubMed:20148899). {ECO:0000269|PubMed:20148899}.

Ptm: The two subunits are derived from the precursor sequence by an autocatalytic mechanism. {ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:8044845}.

Ptm: Ubiquitinated via 'Lys-11'-linked polyubiquitination. Deubiquitinated by USP8. {ECO:0000269|PubMed:30065070}.

Ptm: Cleavage in the interdomain linker region is required to induce pyroptosis. {ECO:0000269|PubMed:32051255}.

Similarity: Belongs to the peptidase C14A family. {ECO:0000305}.

Sequence caution: Sequence=AAT72297.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=AAT72297.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Thiol protease involved in a variety of inflammatory processes by proteolytically cleaving other proteins, such as the precursors of the inflammatory cytokines interleukin-1 beta (IL1B) and interleukin 18 (IL18) as well as the pyroptosis inducer Gasdermin-D (GSDMD), into active mature peptides (PubMed:15326478, PubMed:1574116, PubMed:7876192, PubMed:15498465, PubMed:26375003, PubMed:32051255). Plays a key role in cell immunity as an inflammatory response initiator: once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage of the two inflammatory cytokines IL1B and IL18, releasing the mature cytokines which are involved in a variety of inflammatory processes (PubMed:1574116, PubMed:7876192, PubMed:15498465, PubMed:15326478, PubMed:32051255). Cleaves a tetrapeptide after an Asp residue at position P1 (PubMed:1574116, PubMed:7876192, PubMed:15498465). Also initiates pyroptosis, a programmed lytic cell death pathway, through cleavage of GSDMD (PubMed:26375003). In contrast to cleavage of interleukins IL1B and IL1B, recognition and cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP1 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32051255, PubMed:32109412, PubMed:32553275). Upon inflammasome activation, during DNA virus infection but not RNA virus challenge, controls antiviral immunity through the cleavage of CGAS, rendering it inactive (PubMed:28314590). In apoptotic cells, cleaves SPHK2 which is released from cells and remains enzymatically active extracellularly (PubMed:20197547). {ECO:0000269\|PubMed:15326478, ECO:0000269\|PubMed:15498465, ECO:0000269\|PubMed:1574116, ECO:0000269\|PubMed:20197547, ECO:0000269\|PubMed:26375003, ECO:0000269\|PubMed:28314590, ECO:0000269\|PubMed:32051255, ECO:0000269\|PubMed:32109412, ECO:0000269\|PubMed:32553275, ECO:0000269\|PubMed:7876192}.



Function:		[Isoform Delta]: Apoptosis inactive. {ECO:0000269\|PubMed:7876192}.



Function:		[Isoform Epsilon]: Apoptosis inactive. {ECO:0000269\|PubMed:7876192}.


Catalytic activity:		Reaction=Strict requirement for an Asp residue at position P1 and has a preferred cleavage sequence of Tyr-Val-Ala-Asp-\|-.; EC=3.4.22.36; Evidence={ECO:0000269\|PubMed:1574116};
Activity regulation:		(Microbial infection) Specifically inhibited by the cowpox virus Crma protein. {ECO:0000269\|PubMed:1339309}.
Subunit:		Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-1 subunit p20) and a 10 kDa (Caspase-1 subunit p10) subunit (PubMed:8044845, PubMed:9987822, PubMed:32109412, PubMed:32553275). May be a component of the inflammasome, a protein complex which also includes PYCARD, CARD8 and NLRP2 and whose function would be the activation of proinflammatory caspases (PubMed:15030775, PubMed:33420033). Interacts with CARD8; interacts with the released C-terminus of CARD8 which forms an inflammasome and directly activates CASP1 to promote pyroptosis (PubMed:32051255). Both the p10 and p20 subunits interact with MEFV (PubMed:16785446). Interacts with CARD17/INCA and CARD18 (PubMed:15383541, PubMed:11051551). Interacts with SERPINB1; this interaction regulates CASP1 activity (PubMed:30692621). {ECO:0000269\|PubMed:11051551, ECO:0000269\|PubMed:15030775, ECO:0000269\|PubMed:15383541, ECO:0000269\|PubMed:16785446, ECO:0000269\|PubMed:30692621, ECO:0000269\|PubMed:32051255, ECO:0000269\|PubMed:32109412, ECO:0000269\|PubMed:32553275, ECO:0000269\|PubMed:8044845, ECO:0000269\|PubMed:9987822}.
Subunit:		[Caspase-1 subunit p20]: Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-1 subunit p20) and a 10 kDa (Caspase-1 subunit p10) subunit (PubMed:8044845, PubMed:32109412, PubMed:32553275). Can form a heterodimer with isoform epsilon which then has an inhibitory effect (PubMed:7876192). {ECO:0000269\|PubMed:32109412, ECO:0000269\|PubMed:32553275, ECO:0000269\|PubMed:7876192, ECO:0000269\|PubMed:8044845}.
Subunit:		[Caspase-1 subunit p10]: Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-1 subunit p20) and a 10 kDa (Caspase-1 subunit p10) subunit. {ECO:0000269\|PubMed:32109412, ECO:0000269\|PubMed:32553275, ECO:0000269\|PubMed:8044845}.
Subunit:		[Isoform Epsilon]: Can form a heterodimer with Caspase-1 subunit p20 which then has an inhibitory effect. {ECO:0000269\|PubMed:7876192}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:20197547}. Cell membrane {ECO:0000269\|PubMed:20197547}.
Tissue specificity:		Expressed in larger amounts in spleen and lung. Detected in liver, heart, small intestine, colon, thymus, prostate, skeletal muscle, peripheral blood leukocytes, kidney and testis. No expression in the brain. {ECO:0000269\|PubMed:15498465}.
Induction:		Transcription and translation induced by M.tuberculosis and a number of different M.tuberculosis components; EsxA is the most potent activator tested (at protein level) (PubMed:20148899). {ECO:0000269\|PubMed:20148899}.
Ptm:		The two subunits are derived from the precursor sequence by an autocatalytic mechanism. {ECO:0000269\|PubMed:32109412, ECO:0000269\|PubMed:8044845}.
Ptm:		Ubiquitinated via 'Lys-11'-linked polyubiquitination. Deubiquitinated by USP8. {ECO:0000269\|PubMed:30065070}.
Ptm:		Cleavage in the interdomain linker region is required to induce pyroptosis. {ECO:0000269\|PubMed:32051255}.
Similarity:		Belongs to the peptidase C14A family. {ECO:0000305}.
Sequence caution:		Sequence=AAT72297.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=AAT72297.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305};