Caspase-8

Definition:

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. 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-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. Cleaves PARP1 and PARP2.; [Isoform 5]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.; [Isoform 6]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.; [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.; [Isoform 8]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.

References:

[1]. Sonja Blasche, et al. The E. coli effector protein NleF is a caspase inhibitor. PLoS One. 2013;8(3):e58937. [Content Brief]

[2]. M Muzio, et al. FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens. J Biol Chem. 1997 Jan 31;272(5):2952-6. [Content Brief]

[3]. Jean-Bernard Denault, et al. Engineered hybrid dimers: tracking the activation pathway of caspase-7. Mol Cell. 2006 Aug;23(4):523-33. [Content Brief]

[4]. Panfeng Tao, et al. A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature. 2020 Jan;577(7788):109-114. [Content Brief]

[5]. Najoua Lalaoui, et al. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature. 2020 Jan;577(7788):103-108. [Content Brief]

[6]. J P Medema, et al. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J. 1997 May 15;16(10):2794-804. [Content Brief]

[7]. Ting Peng, et al. Pathogen hijacks programmed cell death signaling by arginine ADPR-deacylization of caspases. Mol Cell. 2022 May 19;82(10):1806-1820.e8. [Content Brief]

[8]. Yaxin Liu, et al. Calmodulin Binding Activates Chromobacterium CopC Effector to ADP-Riboxanate Host Apoptotic Caspases. mBio. 2022 Jun 28;13(3):e0069022. [Content Brief]

[9]. M P Boldin, et al. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996 Jun 14;85(6):803-15. [Content Brief]

[10]. Daisuke Himeji, et al. Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood. 2002 Jun 1;99(11):4070-8. [Content Brief]

[11]. M Muzio, et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell. 1996 Jun 14;85(6):817-27. [Content Brief]

[12]. T Fernandes-Alnemri, et al. In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7464-9. [Content Brief]

[13]. S M Srinivasula, et al. Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14486-91. [Content Brief]

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