Caspases (Cysteine-ASPartic proteASES) are a group of proteases that cleave their substrates after specific short tetrapeptide motifs ending with an aspartic acid residue. Based on their functions, caspases can be categorized into two groups, inflammatory caspases, which regulate inflammatory responses, and apoptotic caspases, which are involved in apoptosis. The apoptotic caspases can further be subdivided into initiator caspases (caspase-8, −9 and −10 in human) and executioner caspases (caspase-3, −6 and −7 in human). All the caspases are synthesized as inactive zymogens consisting of a pro-domain, a large subunit and a small subunit. The pro-domain in an executioner caspase contains less than 30 amino acids, while the pro-domain of an initiator caspase is longer (∼ 150–200 amino acids), consisting of either two death effector domains (DED) or a caspase activation and recruitment domain (CARD)[1], [2]. The cascade composed by initiator caspases and executioner caspases plays a key role in apoptosis.

Apoptosis can be triggered by interaction between death receptors and their ligands (extrinsic pathway) or by mitochondrial outer membrane permeabilization (MOMP) induced by diverse physical or chemical stress (intrinsic pathway) (Fig. 1). In both pathways, initiator caspases are recruited to a multi-protein signaling platform (death-inducing signaling complex in the extrinsic pathway or apoptosome in the intrinsic pathway) where they are activated through dimerization [1], [2]. The main task of initiator caspases in apoptosis is to cleave and activate executioner caspases. In addition, caspase-8, the initiator caspase activated by death receptors, connects the extrinsic pathway and the intrinsic pathway by cleaving the BH3-only protein Bid. Cleavage of Bid by caspase-8 generates a 15 kDa C-terminal fragment tBid [3], [4], which can induce MOMP through activating BAK and BAX [5], [6], [7] or directly by itself [8].

Executioner caspases are present in healthy cells as inactive pro-caspase dimers. Cleavage by initiator caspases results in conformational change and activation of executioner caspases [1], [2]. Active executioner caspases can in turn enhance MOMP and activation of initiator caspases, forming a positive feedback loop that ensures rapid and full activation of caspases and efficient killing [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. Live monitoring of lethal executioner caspase activation during apoptosis with fluorescence resonance energy transfer (FRET) sensor has revealed that once initiated, activation of executioner caspases peaks within 15 min [19], [20], [21]. Active executioner caspases cleave hundreds or even thousands of protein substrates, leading to characteristic morphological changes of apoptosis such as chromatin condensation, DNA fragmentation, plasma membrane blebbing and formation of apoptotic bodies (Fig. 1) [22]. Therefore, executioner caspase activation was once considered “a point of no return” in the apoptotic process [23]. However, activation of executioner caspases also leads to production of autonomous and non-autonomous pro-survival signals [24]. Accumulating evidences have demonstrated that cells can survive from stress-induced activation of executioner caspases [25]. Here we review studies on cell death and survival from executioner caspase activation in response to stress. Executioner caspases also play important non-apoptotic roles in cell differentiation and cell remodeling, which has been reviewed previously (for example in [24], [26]) and is not discussed in this review.