Evolution of caspase-mediated cell death and differentiation: twins separated at birth

Abstract

The phenotypic and biochemical similarities between caspase-mediated apoptosis and cellular differentiation are striking. They include such diverse phenomenon as mitochondrial membrane perturbations, cytoskeletal rearrangements and DNA fragmentation. The parallels between the two disparate processes suggest some common ancestry and highlight the paradoxical nature of the death-centric view of caspases. That is, what is the driving selective pressure that sustains death-inducing proteins throughout eukaryotic evolution? Plausibly, caspase function may be rooted in a primordial non-death function, such as cell differentiation, and was co-opted for its role in programmed cell death. This review will delve into the links between caspase-mediated apoptosis and cell differentiation and examine the distinguishing features of these events. More critically, we chronicle the evolutionary origins of caspases and propose that caspases may have held an ancient role in mediating the fidelity of cell division/differentiation through its effects on proteostasis and protein quality control.

Figure 1

Conservation of caspase signaling cascades through eukaryotic evolution. The effector caspases (purple), caspase-3 and -7 (mammals), drICE and Dcp1 (Drosophila), and CED-3 (functions as both initiator and effector caspase in C. elegans) dictate a diverse set of physiological outcomes including caspase-mediated PCD, differentiation and cell cycle regulation. The lone caspase-like protein within budding yeast, Yca1, acts in a similar manner as the above effector caspases and is involved in yeast cell death, cell cycle progression and proteostasis. Upstream of the effector caspases there are homologous proteins that partake in caspase signaling, including initiator caspases (green), caspase activators (red) and related anti-apoptotic proteins (blue)

Figure 2

The role of caspase in establishing asymmetric cell division: potential primordial link between caspase function and cell differentiation. Caspase-dependent protein processing in the budding yeast, S. cerevisiae, is essential for proteostasis and the destruction of protein aggregates that would be detrimental to cell survival. Upon cytokenesis, the yeast metacaspase, Yca1, is tasked at preventing accumulated protein aggregates from entering the newly formed daughter cell, thereby increasing progeny fitness. This is similar to the emerging role of eukaryotic caspases in regulating stem cell symmetrical/asymmetrical division. To date, caspases have been associated with the degradation of the ESC pluripotency factor, Nanog, as well as the muscle cell lineage-specific factor, Pax7. Caspase targeting of these factors is essential for establishing asymmetric cell division and the initiation of cell differentiation. There is also evidence that suggests that caspase cleavage activation of PKCζ (PKCz in figure) – a known factor in mediating polarity cues in differentiating neuroblasts – is critical in initiating asymmetric cell division. Moreover, activation of the mammalian Ste20-like kinase (MST1) via caspase cleavage, which was recently established to be important to the fidelity of muscle cell differentiation, may be involved in polarity signaling during asymmetric cell division. This is based on previous work on Drosophila neuronal cells, where polarity cues relied, in part, on the activated homolog for MST1, Hippo.^, The conservation of caspase involvement in cell polarity signaling is further supported by the caspase-dependent cleavage of LIN-14 and LIN-28 in C. elegans seam cells, with both proteins being critically involved in symmetric/asymmetric cell divisions. Caspase-dependent protein processing during asymmetric cell division may represent the origins of caspase involvement in cell differentiation, and may precede the death-centric functions of these proteases