Figure: Mammalian caspase family and C. elegans caspase CED- 3 [1]. All mammalian caspases are of human origin except for murine caspase-11 and -12, for which no human counterparts have been identified yet. Substrate preferences at the P1 to P4 positions are indicated (amino acids in one-letter-code). Based on the substrate specificity, caspases are divided into three groups (indicated in parentheses). Cyan: death effector domains (DED), magenta: caspase recruitment domain (CARD).

Caspases mediating apoptosis can be discriminated into “initiator” caspases, which are activated by cellular signaling, and “effector” or “executioner” caspases, which are activated by the initiator caspases [6]. The latter takes place by proteolytic processing at aspartic acid residues and following a proteolytic cascade [1, 4]. Besides their role in apoptosis, caspases are important for a number of non-apoptotic cellular processes. The latter include non-apoptotic cell death like necroptosis, autophagy and pyroptosis, but also the activation of inflammasomes and diverse events during tissue differentiation [7, 8].

Initiation Pathways

Two major pathways are known for activation of the initiator caspases. The “intrinsic” or mitochondrial pathway is a response to cellular stresses like DNA damage or cytotoxins [6]. Regulated by the B-cell lymphoma 2 (Bcl-2) family of proteins, several factors form the “apoptosome” and recruit and activate initiator caspase-9 [9]. In the “extrinsic” or death receptor mediated pathway, receptors of the tumor necrosis factor (TNF) receptor superfamily are activated in the first step [10]. This leads to formation of the death-inducing signaling complex (DISC) and activation of specific initiator caspases, which is caspase -8 in humans and mice [6, 11]. The protein-protein interactions for formation of the DISC are established by death effector domains (DEDs), which caspases of the extrinsic pathway have in common with other DISC-forming protein components [6, 12]. In many cases, the formation of caspase oligomers, or the interaction of caspases with other proteins involves caspase recruitment domains (CARDs). Both, DEDs and CARDs comprise “death fold” motifs, which are found in other proteins as well, modulating apoptosis and inflammation [12]. Once activated the initiator caspases process and activate one or more of the effector caspases. All initiation pathways thereby seem to converge at the same execution cascade, with caspase -3 as the main effector caspase downstream [3, 13, 14]. In the following, the activated effector caspases cleave various cellular proteins, which finally leads to apoptotic cell death [15]. Since they are implicated in manifold and severe pathological disorders, factors modulating apoptosis are interesting but likewise challenging therapeutic targets [16-19]. Bachem offers a broad selection of inhibitors and research peptides, which are used to investigate the underlying principles of caspase inhibition and –activation and their impact on regulated cell death.

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References

[1]           H.Y. Chang and X. Yang, Proteases for cell suicide: functions and regulation of caspases. Microbiology and Molecular Biology Reviews, 64(4), 821-46 (2000)

[2]           M.G. Grütter, Caspases: key players in programmed cell death. Current Opinion in Structural Biology, 10(6), 649-55 (2000)

[3]           B. Zhivotovsky, Caspases: the enzymes of death. Essays in Biochemistry, 3925-40 (2003)

[4]           H.R. Stennicke and G.S. Salvesen, Properties of the caspases. Biochimica et Biophysica Acta, 1387(1-2), 17-31 (1998)

[5]           D.W. Nicholson and N.A. Thornberry, Caspases: killer proteases. Trends in Biochemical Sciences, 22(8), 299-306 (1997)

[6]           A. Degterev et al., A decade of caspases. Oncogene, 22(53), 8543-67 (2003)

[7]           S. Shalini et al., Old, new and emerging functions of caspases. Cell Death and Differentiation, 22(4), 526-39 (2015)

[8]           S.M. Man and T.D. Kanneganti, Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nature Reviews Immunology, 16(1), 7-21 (2016)

[9]           J.M. Adams and S. Cory, life-or-death decisions by the Bcl-2 protein family. Trends in Biochemical Sciences, 26(1), 61 (2001)

[10]           U. Gaur and B.B. Aggarwal, Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. Biochemical Pharmacology, 66(8), 1403-8 (2003)

[11]           E.E. Varfolomeev et al., Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity, 9(2), 267-76 (1998)

[12]           J.S. Riley et al., DED or alive: assembly and regulation of the death effector domain complexes. Cell Death and Disease, 6e1866 (2015)

[13]           K.M. Boatright and G.S. Salvesen, Caspase activation. Current Opinion in Cell Biology, (70), 233-42 (2003)

[14]           H.R. Stennicke and G.S. Salvesen, Caspases – controlling intracellular signals by protease zymogen activation. Biochimica et Biophysica Acta, 1477(1-2), 299-306 (2000)

[15]           E.A. Slee et al., Serial killers: ordering caspase activation events in apoptosis. Cell Death and Differentiation, 6(11), 1067-74 (1999)

[16]           B.R. Gastman, Apoptosis and its clinical impact. Head & Neck, 23(5), 409-25 (2001)

[17]           J.C. Reed, Apoptosis-regulating proteins as targets for drug discovery. Trends in Molecular Medicine, 7(7), 314-9 (2001)

[18]           A. Philchenkov, Caspases: potential targets for regulating cell death. Journal of Cellular and Molecular Medicine, 8(4), 432-44 (2004)

[19]           M.J. Roy et al., Cell death and the mitochondria: therapeutic targeting of the BCL-2 family-driven pathway. British Journal of Pharmacology, 171(8), 1973-87 (2014)

Caspases are involved in apoptosis, play a role in inflammation and contribute to biological processes. An increase in apoptosis and caspase activity are associated with many different disorders such as hepatic and transplant injuries, myocardial infarction and neurodegenerative diseases. Pro-inflammatory caspases are involved in arthritis and psoriasis. Diminished caspase activity is associated with cancers (1). While there are currently no approved peptide drugs based on caspase inhibition or activation, there are several in preclinical to Phase II development. Peptide-based drug candidates known to be caspase inhibitors and activators are shown in Table 1 below.

Table 1: Peptidic Caspase Inhibitors and Activators in Development Preclinical to Pending Approval (2)