Protein: Caspase-8 (CASP-8) (EC 3.4.22.61) [Cleaved into: Caspase-8 subunit p18; Caspase-8 subunit p10] (Q9JHX4)
Organism: Rattus norvegicus (Rat)
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. Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (By similarity). Binding to the adapter molecule FADD recruits it to either receptor TNFRSF6/FAS mediated or TNFRSF1A. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation (By similarity). The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (By similarity). Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (By similarity). In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-325', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (By similarity). 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 (By similarity). Cleaves PARP1 and PARP2 (By similarity).
Subcellular location: Cytoplasm {ECO:0000269|PubMed:10197541}. Nucleus {ECO:0000269|PubMed:10197541}.
Sequence: MDFHSCLYDIAERLGNEELAALKFLCLDHIPQKKQESINDVLVLFQRLQEEGMLEEDNLSFLKELLFHISRRDLLSRVLKSSPEEMVRELQVLGKAQVSAYRVMLFKLSEDMDKEDLKSFKFLLITEIPKCKLQDNSSLLDIFVEMEKRTILAENNLVTLKSICFRVNRSLLGRIDDYERSSTERRMSTEGGEELPVSVLDEVTIKMQDMWDSPGEQESESLNSDNVYQMKSKPRGYCLIFNNNNFSKAREDIPKLSNMRDRKGTNYDEEALSKTFKELHFEIVSFSDCTASQIHEVLVSYQSKDHKGKDCFICCILSHGDKGIVYGTDGKEASIYELTSYFTGSKCPSLAGKPKIFFIQACQGNNFQKAVPVPDETGLEQEHVLEEDSSSYKNYIPDEADFLLGMATVKNCVSYRDPTRGTWYIQSLCQSLRERCPRGEDILSILTGVNYDVSNKDNPRNMGKQMPQPIFTLRKKLFFPPN
InterPro domains: - IPR011600: Peptidase C14, caspase domain (domain) [235-478]
- IPR011029: Death-like domain superfamily (homologous_superfamily) [1-188]
- IPR033170: Caspase-8, death effector domain 1 (domain) [3-84]
- IPR015917: Peptidase C14A, caspase catalytic domain (domain) [227-481]
- IPR016129: Peptidase family C14A, His active site (active_site) [306-320]
- IPR002138: Peptidase C14, caspase non-catalytic subunit p10 (domain) [396-481]
- IPR033139: Peptidase family C14A, cysteine active site (active_site) [353-364]
- IPR001875: Death effector domain (domain) [1-180]
- IPR029030: Caspase-like domain superfamily (homologous_superfamily) [226-481]
- IPR001309: Peptidase C14, p20 domain (domain) [234-366]
Interaction partners: - Receptor-interacting serine/threonine-protein kinase 1
- Receptor-interacting serine/threonine-protein kinase 3
- Tumor necrosis factor receptor type 1-associated DEATH domain protein
- FAS-associated death domain protein
- Tumor necrosis factor receptor superfamily member 6
- CASP8 and FADD-like apoptosis regulator
- Caspase-3
- Caspase-1
- Tumor necrosis factor ligand superfamily member 6
- B-cell lymphoma/leukemia 10
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0044877 (protein-containing complex binding), GO:0005515 (protein binding), GO:0019899 (enzyme binding), GO:0005102 (signaling receptor binding), GO:0005126 (cytokine receptor binding), GO:0002020 (protease binding), GO:0032813 (tumor necrosis factor receptor superfamily binding), GO:0005123 (death receptor binding)
Biological Process (BP): GO:0008150 (biological process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0008152 (metabolic process), GO:0048519 (negative regulation of biological process), GO:0048856 (anatomical structure development), GO:0009653 (anatomical structure morphogenesis), GO:0042221 (response to chemical), GO:0051240 (positive regulation of multicellular organismal process), GO:0006807 (nitrogen compound metabolic process), GO:0071840 (cellular component organization or biogenesis), GO:0051239 (regulation of multicellular organismal process), GO:0048646 (anatomical structure formation involved in morphogenesis), GO:0050793 (regulation of developmental process), GO:0009719 (response to endogenous stimulus), GO:0008219 (cell death), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0051716 (cellular response to stimulus), GO:0023051 (regulation of signaling), GO:0048523 (negative regulation of cellular process), GO:0048869 (cellular developmental process), GO:0009628 (response to abiotic stimulus), GO:0023056 (positive regulation of signaling), GO:0007275 (multicellular organism development), GO:0048584 (positive regulation of response to stimulus), GO:0019222 (regulation of metabolic process), GO:0071704 (organic substance metabolic process), GO:0009056 (catabolic process), GO:0009893 (positive regulation of metabolic process), GO:0065009 (regulation of molecular function), GO:0006950 (response to stress), GO:0051094 (positive regulation of developmental process), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:0010942 (positive regulation of cell death), GO:0012501 (programmed cell death), GO:0060548 (negative regulation of cell death), GO:0048468 (cell development), GO:0030154 (cell differentiation), GO:0080134 (regulation of response to stress), GO:0048731 (system development), GO:0048513 (animal organ development), GO:0009966 (regulation of signal transduction), GO:0060255 (regulation of macromolecule metabolic process), GO:0071495 (cellular response to endogenous stimulus), GO:0001817 (regulation of cytokine production), GO:0060041 (retina development in camera-type eye), GO:0009725 (response to hormone), GO:0035295 (tube development), GO:0010035 (response to inorganic substance), GO:1904018 (positive regulation of vasculature development), GO:0022603 (regulation of anatomical structure morphogenesis), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0016043 (cellular component organization), GO:0001819 (positive regulation of cytokine production), GO:1901575 (organic substance catabolic process), GO:0071496 (cellular response to external stimulus), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0035239 (tube morphogenesis), GO:0009967 (positive regulation of signal transduction), GO:0050790 (regulation of catalytic activity), GO:0044093 (positive regulation of molecular function), GO:1901564 (organonitrogen compound metabolic process), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0001568 (blood vessel development), GO:0019538 (protein metabolic process), GO:0080135 (regulation of cellular response to stress), GO:1901700 (response to oxygen-containing compound), GO:0043170 (macromolecule metabolic process), GO:0010033 (response to organic substance), GO:0001525 (angiogenesis), GO:2000026 (regulation of multicellular organismal development), GO:0104004 (cellular response to environmental stimulus), GO:0010941 (regulation of cell death), GO:1901698 (response to nitrogen compound), GO:0010646 (regulation of cell communication), GO:0070887 (cellular response to chemical stimulus), GO:0033554 (cellular response to stress), GO:0009889 (regulation of biosynthetic process), GO:0010647 (positive regulation of cell communication), GO:0031323 (regulation of cellular metabolic process), GO:0080090 (regulation of primary metabolic process), GO:1901652 (response to peptide), GO:0097305 (response to alcohol), GO:0030030 (cell projection organization), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0051246 (regulation of protein metabolic process), GO:0043067 (regulation of programmed cell death), GO:0001944 (vasculature development), GO:0030163 (protein catabolic process), GO:0048545 (response to steroid hormone), GO:0070302 (regulation of stress-activated protein kinase signaling cascade), GO:0010468 (regulation of gene expression), GO:0048666 (neuron development), GO:0009057 (macromolecule catabolic process), GO:0007399 (nervous system development), GO:0072359 (circulatory system development), GO:0036293 (response to decreased oxygen levels), GO:1902533 (positive regulation of intracellular signal transduction), GO:0051252 (regulation of RNA metabolic process), GO:0043085 (positive regulation of catalytic activity), GO:1901701 (cellular response to oxygen-containing compound), GO:0010467 (gene expression), GO:1901216 (positive regulation of neuron death), GO:0010038 (response to metal ion), GO:1901216 (positive regulation of neuron death), GO:0071417 (cellular response to organonitrogen compound), GO:1901565 (organonitrogen compound catabolic process), GO:0006508 (proteolysis), GO:0071310 (cellular response to organic substance), GO:0043068 (positive regulation of programmed cell death), GO:0062197 (cellular response to chemical stress), GO:1901699 (cellular response to nitrogen compound), GO:1901214 (regulation of neuron death), GO:0010628 (positive regulation of gene expression), GO:0032652 (regulation of interleukin-1 production), GO:0043434 (response to peptide hormone), GO:0022008 (neurogenesis), GO:0032870 (cellular response to hormone stimulus), GO:0010243 (response to organonitrogen compound), GO:0048514 (blood vessel morphogenesis), GO:0044265 (cellular macromolecule catabolic process), GO:0033993 (response to lipid), GO:0006915 (apoptotic process), GO:0031326 (regulation of cellular biosynthetic process), GO:0051247 (positive regulation of protein metabolic process), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0045765 (regulation of angiogenesis), GO:0014070 (response to organic cyclic compound), GO:0042542 (response to hydrogen peroxide), GO:0006996 (organelle organization), GO:0000302 (response to reactive oxygen species), GO:0030182 (neuron differentiation), GO:1902531 (regulation of intracellular signal transduction), GO:0042981 (regulation of apoptotic process), GO:0031960 (response to corticosteroid), GO:0052547 (regulation of peptidase activity), GO:2001141 (regulation of RNA biosynthetic process), GO:0043523 (regulation of neuron apoptotic process), GO:0051092 (positive regulation of NF-kappaB transcription factor activity), GO:0097746 (blood vessel diameter maintenance), GO:0051896 (regulation of protein kinase B signaling), GO:0035296 (regulation of tube diameter), GO:0043410 (positive regulation of MAPK cascade), GO:0048699 (generation of neurons), GO:0043525 (positive regulation of neuron apoptotic process), GO:0043065 (positive regulation of apoptotic process), GO:0071375 (cellular response to peptide hormone stimulus), GO:0120036 (plasma membrane bounded cell projection organization), GO:0006355 (regulation of DNA-templated transcription), GO:0043632 (modification-dependent macromolecule catabolic process), GO:0051603 (proteolysis involved in protein catabolic process), GO:0071407 (cellular response to organic cyclic compound), GO:0071396 (cellular response to lipid), GO:1901653 (cellular response to peptide), GO:0043122 (regulation of I-kappaB kinase/NF-kappaB signaling), GO:0031175 (neuron projection development), GO:1990776 (response to angiotensin), GO:0070301 (cellular response to hydrogen peroxide), GO:0016485 (protein processing), GO:0010952 (positive regulation of peptidase activity), GO:0052548 (regulation of endopeptidase activity), GO:0031638 (zymogen activation), GO:1903506 (regulation of nucleic acid-templated transcription), GO:0019941 (modification-dependent protein catabolic process), GO:0010950 (positive regulation of endopeptidase activity), GO:2000116 (regulation of cysteine-type endopeptidase activity), GO:2001056 (positive regulation of cysteine-type endopeptidase activity), GO:0043281 (regulation of cysteine-type endopeptidase activity involved in apoptotic process), GO:0043280 (positive regulation of cysteine-type endopeptidase activity involved in apoptotic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0032991 (protein-containing complex), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0016020 (membrane), GO:0005829 (cytosol), GO:0005737 (cytoplasm), GO:0071944 (cell periphery), GO:0098796 (membrane protein complex), GO:0098797 (plasma membrane protein complex), GO:0098857 (membrane microdomain), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0005886 (plasma membrane), GO:0045121 (membrane raft), GO:0043231 (intracellular membrane-bounded organelle), GO:0005634 (nucleus)