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.