Programmed cell death (apoptosis) is a crucial step in maintaining the homeostatic balance in multicellular organisms [1].The apoptotic pathway is characterized by the systematic destruction of intracellular structures without causing damages to the cells nearby, and it entails a complicated cascade of events orchestrated by various enzymes known as the caspases, which are members of a highly conserved family of cysteinyl aspartate proteases[2]. It has been discovered that the mammalian caspase gene family contains at least 14 members, among which 11 are found in humans [3].
Casp-8 is an initiator caspase that is involved in the extrinsic apoptotic pathway. The pathway starts with the binding of extracellular ligands (members of the Tumour Necrosis Factor (TNF) superfamily) to their corresponding receptors at the cell surface[4], including Fas (CD-95 or APO-1) [5]. TNF receptor 1 & 2 [6] , and TRAIL (TNF-Related Apoptosis-Inducing Ligand) receptors (DRs) [7] etc. The ligation of pro-apoptotic cytokines to these death receptors, particularly to Fas, leads to immediate receptor trimerization on the cell surface, which in turn results in the binding of adaptor proteins Fas-Associated Death Domains (FADD) to the receptors. The subsequent addition of casp-8 to the resultant Death-Inducing Signalling Complex (DISC) is achieved via homotypic interaction between the two death-effector domains (DEDs) of the caspase-8 with FADD [8],[9].
Upon receiving the external death signals, the activated casp-8 can directly cleave and activate executioner caspases, namely casp-3, casp-7 and possibly casp-6, which in turn act on a series of downstream effectors via proteolysis to initiate apoptosis. Apart from the extrinsic pathway, casp-8 can also mediate the mitochondrion-dependent intrinsic pathway via the cleavage of BID, a member of the BH3-domain containing Bcl-2 family[10]. The resultant truncated BID (tBID) can enter the mitochondria and induce the leakage of cytochrome c, initiating apoptosis via the activation of another initiator caspase, casp-9 [10].
Like other caspases, caspase-8 often exists as an inactive precursor called the procaspase-8 zymogen, which consists of an N-terminal pro-domain in which the two tandem DEDs reside, as well as a C-terminal catalytic domain [11]. The C-terminal protease domain consists of a large (20KDa) α subunit (p18), and a small (12KDa) β subunit (p10). These subunits would aggregate together with those from another casp-8 to form the α2β2 heterotetramer upon proteolytic cleavage [12] . Based on the recently proposed proximity-driven model [13] , procaspase-8 is subject to dimerization immediately after cell death signalling, forming a homodimeric complex that is more prone to effective cleavage by other procaspase-8 dimers [14]. The full activation of caspase-8 is characterized by a two-step mechanism: firstly, Asp374 and Asp384 are cleaved with the removal of the linker region between p18 & p10; this would facilitate the subsequent cleavage at Asp126 and Asp216 between p18 & the pro-domain [13],[14]. The mature enzyme is released as a heterotetramer consisting only of p18 and p10 subunits.
Introduction
Caspase-8 in the apoptotic pathway
BID as a downstream substrate of Casp-8
Activation of Procaspase-8
References
[1] Raff M. Cell suicide for beginners. Nature. 1998;396(6707):119-122.
[2] Grütter MG. Caspases: key players in programmed cell death. Current Opinion Structural Biology. 2000;10(6):649-55.
[3] Siegel RM. Caspases at the crossroads of immune-cell life and death. Natuture Review Immunology. 2006; 6(4):308-17.
[4] Fuchs Y, Steller H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nature Review Molecular Cell Biology. 2015; 16(6): 329-344.
[5] Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991; 26;66(2):233-43.
[6] Loetscher H, Pan YC, Lahm HW, Gentz R, Brockhaus M, Tabuchi H, Lesslauer W. Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor. Cell. 1990; 61(2):351-9.
[7] Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science. 1997; 277(5327):818-21.
[8] Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell. 1996; 85(6):817-27.
[9] Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996; 85(6):803-15.
[10] Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998; 94(4):491-501.
[11] Kantari C, Walczak H. Caspase-8 and bid: caught in the act between death receptors and mitochondria. Biochim Biophys Acta. 201;1813(4):558-63.
[12] Wang ZB, Liu YQ, Cui YF. Pathways to caspase activation. Cell Biol Int. 2005; 29(7):489-96.
[13] Keller N, Mares J, Zerbe O, Grütter MG. Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation. Structure. 2009;17(3):438-48.
[14] Pop C, Fitzgerald P, Green DR, Salvesen GS. Role of proteolysis in caspase-8 activation and stabilization. Biochemistry. 2007; 46(14):4398-407.
Figure 1:
[15] Ramalho RM, Viana RJ, Low WC, Steer CJ, Rodrigues CM. Bile acids and apoptosis modulation: an emerging role in experimental Alzheimer's disease. Trends Mol Med. 2008 Feb;14(2):54-62.
Figure 2:
[16] Zhao Y, Sui X, Ren H. From procaspase-8 to caspase-8: revisiting structural functions of caspase-8. J Cell Physiol. 2010 Nov;225(2):316-20.
