Caspases are the primary drivers of apoptotic cell death, cleaving cellular proteins that are critical for dismantling the dying cell. Initially translated as inactive zymogenic precursors, caspases are activated in response to a variety of cell death stimuli. In addition to factors required for their direct activation (e.g., dimerizing adaptor proteins in the case of initiator caspases that lie at the apex of apoptotic signaling cascades), caspases are regulated by a variety of cellular factors in a myriad of physiological and pathological settings. For example, caspases may be modified posttranslationally (e.g., by phosphorylation or ubiquitylation) or through interaction of modulatory factors with either the zymogenic or active form of a caspase, altering its activation and/or activity. These regulatory events may inhibit or enhance enzymatic activity or may affect activity toward particular cellular substrates. Finally, there is emerging literature to suggest that caspases can participate in a variety of cellular processes unrelated to apoptotic cell death. In these settings, it is particularly important that caspases are maintained under stringent control to avoid inadvertent cell death. It is likely that continued examination of these processes will reveal new mechanisms of caspase regulation with implications well beyond control of apoptotic cell death.
Apoptosis is a form of programmed cell death that eliminates individual cells within an organism while preserving the overall structure of surrounding tissue. Many of the prominent morphological features of apoptosis were first described in 1972 by Kerr, Wyllie, and Currie (Kerr et al. 1972). However, it was not until the mid-1990s that apoptosis was linked to the activation of the cysteine-dependent aspartate-driven proteases (caspases), which cleave key intracellular substrates to promote cell death (Cerretti et al. 1992; Nicholson et al. 1995; Alnemri et al. 1996; Liu et al. 1996; Thornberry and Lazebnik 1998). Given the critical role that caspases play in dismantling the cell during apoptosis, their activation and subsequent activity are highly regulated. Failure of a cell to properly modulate caspase activity can cause aberrant or untimely apoptotic cell death, potentially leading to carcinogenesis, autoimmunity, neurodegeneration, and immunodeficiency (Thompson 1995; Hanahan and Weinberg 2000; Yuan and Yankner 2000; Li and Yuan 2008).
Caspases are synthesized within the cell as inactive zymogens that lack significant protease activity. Thus, caspases are, in essence, regulated from the moment of protein synthesis in that they are not activated until receipt of specific death stimuli (Earnshaw et al. 1999). The primary structure of a caspase is an amino-terminal prodomain and a carboxy-terminal protease domain, which contains the key catalytic cysteine residue. Caspases are categorized as initiator or effector caspases, based on their position in apoptotic signaling cascades. The initiator caspases (caspase-2, -8, -9, and -10) act apically in cell death pathways and all share long, structurally similar prodomains. This group of enzymes is activated through “induced proximity” when adaptor proteins interact with the prodomains and promote caspase dimerization (Boatright et al. 2003; Baliga et al. 2004; Pop et al. 2006; Riedl and Salvesen 2007; Wachmann et al. 2010). In contrast, the effector caspases (caspase-3, -6, and -7) have shorter prodomains and exist in the cell as preformed, but inactive, homodimers. Following cleavage mediated by an initiator caspase, effector caspases act directly on specific cellular substrates to dismantle the cell. Although many individual caspase substrates have been implicated in specific aspects of cellular destruction (e.g., lamin cleavage is required for the efficient packaging of nuclei into small membrane-bound vesicles), recent proteomic approaches have greatly expanded the known repertoire of proteolytic products generated during apoptosis (Van Damme et al. 2005; Dix et al. 2008; Mahrus et al. 2008). Further work will be needed to confirm these findings and to determine how (or if) all of these substrates participate in the apoptotic process (see Poreba et al. 2013), especially as new details emerge on the relationship between posttranslational modifications, like phosphorylation, and caspase cleavage (Dix et al. 2012).