Cell death proteins: An evolutionary role in cellular adaptation before the advent of apoptosis

Abstract

Programmed cell death (PCD) or apoptosis is a broadly conserved phenomenon in metazoans, whereby activation of canonical signal pathways induces an ordered dismantling and death of a cell. Paradoxically, the constituent proteins and pathways of PCD (most notably the metacaspase/caspase protease mediated signal pathways) have been demonstrated to retain non-death functions across all phyla including yeast, nematodes, drosophila, and mammals. The ancient conservation of both death and non-death functions of PCD proteins raises an interesting evolutionary conundrum: was the primordial intent of these factors to induce cell death or to regulate other cellular adaptations? Here, we propose the hypothesis that apoptotic behavior of PCD proteins evolved or were co-opted from core non-death functions.

Caspase 3 cleavage of Pax7 inhibits self-renewal of satellite cells

“…4 B and C) suggest that CK2 ensures protein stability of Pax7 in proliferating/self-renewing SCs and loss of this kinase function is a key step in initiating myogenic differentiation. Caspase 3 activation is an essential cue for promoting differentiation of committed progenitor cells (12). Our study demonstrates that caspase 3 also acts at a much earlier step in the life cycle of muscle stem cells, by limiting the self-renewal process.…”

“…1A). This temporal activity pattern is reminiscent of caspase 3 activation in other nondeath settings, which include differentiation of committed skeletal myoblasts and stem cells from a variety of lineages, including neuronal and hematopoietic progenitors (12,13,16,17).…”

“…At this juncture, it is salient to consider that the in vivo experimental approach (Adp35 infection) may also result in the loss of caspase 3 activity in transduced non-muscle cell types, a condition that could separately influence the outcome of the regenerative process. For example, caspase 3 activity is an essential requirement for both macrophage and T-cell maturation/differentiation (12), and these immune cell types have been demonstrated to infiltrate damaged muscle tissue and enhance regeneration (20). Therefore, the impaired regeneration that follows Adp35 infection may derive from a loss of caspase function in both SCs and critical immune cell subtypes.…”

“…The caspase 3 protease, originally identified as the central effector of multiple cell death pathways, has been demonstrated to control cell fate determination independent of inducing cell death (11). Transient activation of caspase 3 is essential for inducing the differentiation program across a broad range of lineage restricted progenitor cells (12). In addition, caspase 3 has been observed to limit self-renewal of embryonic stem cells through direct proteolysis and inactivation of the key pluripotency factor Nanog (13).…”

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

“…3 This apparent paradox is best exemplified in the study of cell differentiation, where caspase activity has been shown to modify the differentiation of virtually all somatic cell types tested, across a diverse spectrum of metazoan organisms. 4, 5 …”