Caspase-2 at a glance

Despite two decades of research, the role of caspase-2 in physiology and disease is still poorly understood and controversial. This Cell Science at a Glance article provides an overview of the proposed functions and possible modes of action and regulation of caspase-2. In addition, we will highlight recent findings that may lead to a more comprehensive understanding of this highly conserved protease.Caspase-2, formerly known as ICH-1 (Wang et al., 1994) or NEDD-2 (Kumar et al., 1994), is a highly conserved but functionally poorly defined member of the caspase family, a group of cystein-driven aspartate-directed endopeptidases that are involved in cell death, inflammation and differentiation (Li and Yuan, 2008). Caspase-2 contains an N-terminal caspase recruitment domain (CARD), followed by a large subunit containing the active site (p19) and a small subunit (p12). Thus, caspase-2 is most similar to caspase-9, the initiator of the intrinsic pathway of apoptosis (Li and Yuan, 2008). However, in contrast to 'conventional' initiator caspases, such as caspase-9 or the apical caspase of extrinsic apoptosis, caspase-8, caspase-2 does not process apoptosis effectors that need to be cleaved by initiators for their activation, such as caspase-3, -6 or -7 (Guo et al., 2002; Van de Craen et al., 1999), suggesting that caspase-2 has other substrates (see supplementary material Table S1 and poster). Functionally, caspase-2 has been implicated in the regulation of cell death that is induced by metabolic imbalance, DNA damage, endoplasmic reticulum (ER) stress, mitotic catastrophe and others (reviewed by Krumschnabel et al., 2009; Vakifahmetoglu-Norberg and Zhivotovsky, 2010). The precise function of caspase-2, that is whether it functions as an initiator or effector caspase, is still unknown, and studies on caspase-2 activation are confounded by the fact that caspase-2 is a substrate for caspase-8 as well as for caspase-3 (Paroni et al., 2001; Van de Craen et al., 1999).Similar to other initiator caspases, caspase-2 is activated by proximity-induced oligomerization and trans-cleavage in vitro, and ectopic overexpression is sufficient for its activation in cells (Butt et al., 1998; Read et al., 2002). Endogenous caspase-2 becomes activated as part of different signaling pathways (see poster), some of which depend on the DNA damage-induced formation of the PIDDosome, a complex composed of the CARD- and death domain (DD)-containing adapter protein RAIDD (also known as CRADD) and the p53-inducible DD-containing protein PIDD (also known as LRDD) (Tinel and Tschopp, 2004). However, the significance of this platform in vivo has been challenged by genetic experiments that have demonstrated that PIDD and RAIDD are dispensable for caspase-2 activation (Kim et al., 2009; Manzl et al., 2009), suggesting that alternative modes of caspase-2 activation exist.One such alternative mechanism for caspase-2 activation is possibly mediated by caspase-8 in the death-inducing signaling complex (DISC), which is formed upon CD95 (also known as FAS) receptor clustering (Lavrik et al., 2006; Olsson et al., 2009). The role of caspase-8-mediated caspase-2 activation is, however, controversial, because this event does not necessarily contribute to apoptosis downstream of CD95 (Lavrik et al., 2006). Hence, DISC-dependent caspase-2 activation might be a 'bystander' effect due to its incidental co-recruitment together with that of 'non-canonical' DISC components, such as RAIDD (Duan and Dixit, 1997) or receptor-interacting protein 1 (RIP1) (Ahmad et al., 1997).Other alternative caspase-2 activation mechanisms have been described, including caspase-2 dimerization and subsequent auto-proteolysis, which is induced by K+ efflux in response to bacterial pore-forming toxins (Imre et al., 2012) or heat-shock-triggered protein aggregation (Tu et al., 2006). Furthermore, alternative mRNA splicing (Wang et al., 1994), post-translational modifications, including N-terminal acetylation (Yi et al., 2011) and phosphorylation, appear to impact on and fine-tune these activating events (see poster). The variety of activation mechanisms suggest that caspase-2 becomes activated under diverse conditions of cellular stress, as discussed below.Caspase-2 has been implicated in the induction of cell death by pathogenic bacteria, such as Brucella, Staphylococcus aureus and Salmonella (Chen et al., 2011; Chen and He, 2009). Caspase-2-deficient murine macrophages are protected from Salmonella-induced cell death and show decreased processing of caspase-1, a major driver of inflammation upon infection (Jesenberger et al., 2000). Similarly, cells lacking caspase-2 are also protected from cell death induced by Staphylococcus aureus α-toxin, but the underlying mechanisms that are responsible for escape from cell death have not yet been defined (Imre et al., 2012).In addition to bacterial infections, caspase-2 activation has also been described in the apoptotic response to viral infections by the single-stranded (ss) RNA Rhabdoviridae, such as Maraba virus or vesicular stomatitis virus (VSV). Both viruses are known to induce a strong ER or unfolded protein stress response (UPR), which can lead to apoptosis (Mahoney et al., 2011). Interestingly, by keeping protein levels of RAIDD low, the ER-stress response machinery appears to be able to delay caspase-2-dependent apoptosis upon infection (Mahoney et al., 2011). Under conditions of sustained ER stress, however, the ER stress response factor IRE1α (also known as ERN1), an ER transmembrane kinase-endoribonuclease (RNase), promotes the rapid degradation of microRNAs that target caspase-2 mRNA. This, in turn, causes a rapid induction of caspase-2 protein expression that might contribute to the induction of apoptosis (Upton et al., 2012). Mechanistically, apoptosis induction by caspase-2 has been linked to its cleavage of the pro-apoptotic BCL2 family protein BID into its active form tBID (Guo et al., 2002), and thymocytes