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 (   , ). 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 ( ). 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 . The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases . Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC . 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 (, ). Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-C and -D (GSDMC and GSDMD, respectively): gasdermin cleavage promotes release of the N-terminal moiety that binds to membranes and forms pores, triggering pyroptosis (, ). 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 . Cleaves PARP1 and PARP2 .
Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.
Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.
Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex (Probable). Acts as an inhibitor of the caspase cascade .
Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.
Subcellular locations: Cytoplasm, Nucleus
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.