UniProt functional annotation for Q14790



	UniProt functional annotation for Q14790

UniProt code: Q14790.

Organism: Homo sapiens (Human).

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

Function: Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood (By similarity). Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death (PubMed:23516580, PubMed:8681376, PubMed:8681377, PubMed:9006941, PubMed:9184224, PubMed:8962078). Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (PubMed:8962078, PubMed:9006941). Binding to the adapter molecule FADD recruits it to either receptor TNFRSF6/FAS mediated or TNFRSF1A (PubMed:8681376, PubMed:8681377). The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation (PubMed:9184224). The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (PubMed:9184224). Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (PubMed:9184224). In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-324', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827280, PubMed:31827281). Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-D (GSDMD): GSDMD cleavage promoting release of the N-terminal moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis (By similarity). Initiates pyroptosis following inactivation of MAP3K7/TAK1 (By similarity). Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production (By similarity). May participate in the Granzyme B (GZMB) cell death pathways (PubMed:8755496). Cleaves PARP1 (PubMed:8681376). {ECO:0000250|UniProtKB:O89110, ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281, ECO:0000269|PubMed:8681376, ECO:0000269|PubMed:8681377, ECO:0000269|PubMed:8755496, ECO:0000269|PubMed:8962078, ECO:0000269|PubMed:9006941, ECO:0000269|PubMed:9184224}.

Function: [Isoform 5]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000305|PubMed:8681376}.

Function: [Isoform 6]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000305|PubMed:8681376}.

Function: [Isoform 7]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex (Probable). Acts as an inhibitor of the caspase cascade (PubMed:12010809). {ECO:0000269|PubMed:12010809, ECO:0000305|PubMed:8681376}.

Function: [Isoform 8]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000305|PubMed:8681376}.

Catalytic activity: Reaction=Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).; EC=3.4.22.61; Evidence={ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:8962078};

Activity regulation: CASP8 activity is restricted by RIPK1 (By similarity). Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis (PubMed:23516580). {ECO:0000250|UniProtKB:O89110, ECO:0000269|PubMed:23516580}.

Subunit: Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit (PubMed:10508784). Interacts with FADD, CFLAR and PEA15 (PubMed:10442631). Interacts with TNFAIP8L2 (By similarity). Interacts with CASP8AP2 (PubMed:16378960). Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation (PubMed:15069192). Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium (PubMed:15509781). Interacts with UBR2ca (PubMed:28602583). Interacts with RIPK1 (By similarity). Interacts with stimulated TNFRSF10B; this interaction is followed by CASP8 proteolytic cleavage and activation (PubMed:18846110). {ECO:0000250|UniProtKB:O89110, ECO:0000250|UniProtKB:Q9JHX4, ECO:0000269|PubMed:10442631, ECO:0000269|PubMed:10508784, ECO:0000269|PubMed:15069192, ECO:0000269|PubMed:15509781, ECO:0000269|PubMed:16378960, ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:28602583}.

Subunit: [Isoform 9]: Interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. {ECO:0000269|PubMed:11917123, ECO:0000269|PubMed:9334338}.

Subunit: (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation. {ECO:0000269|PubMed:11427719}.

Subunit: (Microbial infection) Interacts with NleF from pathogenic E.coli. {ECO:0000269|PubMed:23516580}.

Subunit: (Microbial infection) Interacts with molluscum contagiosum virus protein MC160. {ECO:0000269|PubMed:16378960}.

Subunit: (Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation. {ECO:0000269|PubMed:25674983}.

Subunit: (Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation. {ECO:0000269|PubMed:25674983}.

Subcellular location: Cytoplasm {ECO:0000250|UniProtKB:Q9JHX4}. Nucleus {ECO:0000250|UniProtKB:Q9JHX4}.

Tissue specificity: Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle.

Domain: [Isoform 9]: Contains a N-terminal extension that is required for interaction with the BCAP31 complex. {ECO:0000269|PubMed:11917123}.

Ptm: (Microbial infection) Proteolytically cleaved by the cowpox virus CRMA death inhibitory protein. {ECO:0000269|PubMed:8962078}.

Ptm: Generation of the subunits requires association with the death- inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events. {ECO:0000269|PubMed:8962078, ECO:0000269|PubMed:9184224}.

Ptm: Phosphorylation on Ser-387 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. {ECO:0000269|PubMed:20937773}.

Polymorphism: Genetic variations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic variations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner. {ECO:0000269|PubMed:17450141}.

Disease: Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95- induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. {ECO:0000269|PubMed:12353035}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 7]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.

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

Sequence caution: Sequence=CAA66858.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305}; Sequence=CAA66859.1; Type=Miscellaneous discrepancy; 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 that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood (By similarity). Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death (PubMed:23516580, PubMed:8681376, PubMed:8681377, PubMed:9006941, PubMed:9184224, PubMed:8962078). Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (PubMed:8962078, PubMed:9006941). Binding to the adapter molecule FADD recruits it to either receptor TNFRSF6/FAS mediated or TNFRSF1A (PubMed:8681376, PubMed:8681377). The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation (PubMed:9184224). The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (PubMed:9184224). Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (PubMed:9184224). In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-324', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827280, PubMed:31827281). Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-D (GSDMD): GSDMD cleavage promoting release of the N-terminal moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis (By similarity). Initiates pyroptosis following inactivation of MAP3K7/TAK1 (By similarity). Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production (By similarity). May participate in the Granzyme B (GZMB) cell death pathways (PubMed:8755496). Cleaves PARP1 (PubMed:8681376). {ECO:0000250\|UniProtKB:O89110, ECO:0000269\|PubMed:23516580, ECO:0000269\|PubMed:31827280, ECO:0000269\|PubMed:31827281, ECO:0000269\|PubMed:8681376, ECO:0000269\|PubMed:8681377, ECO:0000269\|PubMed:8755496, ECO:0000269\|PubMed:8962078, ECO:0000269\|PubMed:9006941, ECO:0000269\|PubMed:9184224}.



Function:		[Isoform 5]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000305\|PubMed:8681376}.



Function:		[Isoform 6]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000305\|PubMed:8681376}.



Function:		[Isoform 7]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex (Probable). Acts as an inhibitor of the caspase cascade (PubMed:12010809). {ECO:0000269\|PubMed:12010809, ECO:0000305\|PubMed:8681376}.



Function:		[Isoform 8]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000305\|PubMed:8681376}.


Catalytic activity:		Reaction=Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-\|-(Gly/Ser/Ala).; EC=3.4.22.61; Evidence={ECO:0000269\|PubMed:23516580, ECO:0000269\|PubMed:8962078};
Activity regulation:		CASP8 activity is restricted by RIPK1 (By similarity). Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis (PubMed:23516580). {ECO:0000250\|UniProtKB:O89110, ECO:0000269\|PubMed:23516580}.
Subunit:		Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit (PubMed:10508784). Interacts with FADD, CFLAR and PEA15 (PubMed:10442631). Interacts with TNFAIP8L2 (By similarity). Interacts with CASP8AP2 (PubMed:16378960). Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation (PubMed:15069192). Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium (PubMed:15509781). Interacts with UBR2ca (PubMed:28602583). Interacts with RIPK1 (By similarity). Interacts with stimulated TNFRSF10B; this interaction is followed by CASP8 proteolytic cleavage and activation (PubMed:18846110). {ECO:0000250\|UniProtKB:O89110, ECO:0000250\|UniProtKB:Q9JHX4, ECO:0000269\|PubMed:10442631, ECO:0000269\|PubMed:10508784, ECO:0000269\|PubMed:15069192, ECO:0000269\|PubMed:15509781, ECO:0000269\|PubMed:16378960, ECO:0000269\|PubMed:18846110, ECO:0000269\|PubMed:28602583}.
Subunit:		[Isoform 9]: Interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. {ECO:0000269\|PubMed:11917123, ECO:0000269\|PubMed:9334338}.
Subunit:		(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation. {ECO:0000269\|PubMed:11427719}.
Subunit:		(Microbial infection) Interacts with NleF from pathogenic E.coli. {ECO:0000269\|PubMed:23516580}.
Subunit:		(Microbial infection) Interacts with molluscum contagiosum virus protein MC160. {ECO:0000269\|PubMed:16378960}.
Subunit:		(Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation. {ECO:0000269\|PubMed:25674983}.
Subunit:		(Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation. {ECO:0000269\|PubMed:25674983}.
Subcellular location:		Cytoplasm {ECO:0000250\|UniProtKB:Q9JHX4}. Nucleus {ECO:0000250\|UniProtKB:Q9JHX4}.
Tissue specificity:		Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle.
Domain:		[Isoform 9]: Contains a N-terminal extension that is required for interaction with the BCAP31 complex. {ECO:0000269\|PubMed:11917123}.
Ptm:		(Microbial infection) Proteolytically cleaved by the cowpox virus CRMA death inhibitory protein. {ECO:0000269\|PubMed:8962078}.
Ptm:		Generation of the subunits requires association with the death- inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events. {ECO:0000269\|PubMed:8962078, ECO:0000269\|PubMed:9184224}.
Ptm:		Phosphorylation on Ser-387 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. {ECO:0000269\|PubMed:20937773}.
Polymorphism:		Genetic variations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic variations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner. {ECO:0000269\|PubMed:17450141}.
Disease:		Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95- induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. {ECO:0000269\|PubMed:12353035}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 7]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.
Similarity:		Belongs to the peptidase C14A family. {ECO:0000305}.
Sequence caution:		Sequence=CAA66858.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305}; Sequence=CAA66859.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305};