The non-death role of metacaspase proteases

Abstract

The activation of caspase proteases and the targeting of protein substrates act as key steps in the engagement and conduct of apoptosis/programmed cell death. However, the discovery of caspase involvement in diverse non-apoptotic cellular functions strongly suggests that these proteins may have evolved from a core behavior unrelated to the induction of cell death. The presence of similar proteases, termed metacaspases, in single cell organisms supports the contention that such proteins may have co-evolved or derived from a critical non-death function. Indeed, the benefit(s) for single cell life forms to retain proteins solely dedicated to self destruction would be countered by a strong selection pressure to curb or eliminate such processes. Examination of metacaspase biology provides evidence that these ancient protease forerunners of the caspase family also retain versatility in function, i.e., death and non-death cell functions. Here, we provide a critical review that highlights the non-death roles of metacaspases that have been described thus far, and the impact that these observations have for our understanding of the evolution and cellular utility of this protease family.

Keywords: caspase; cell cycle; metacaspase; non-death; proteostasis.

FIGURE 1

Functional overlap of caspase and metacaspase function. Regulation of cell cycle progression is a conserved function for both proteases, suggesting a common evolutionary origin. Additional non-death functions of metacaspases such as the role of Yca1 in proteostasis has yet to be confirmed as a feature of caspase biology.

FIGURE 2

A proposed model of a caspase-dependent mechanism involved in maintaining proteostasis. The interaction of caspases, possibly with yet unidentified additional cofactors, facilitates the regulation of protein aggregates (black circles) within mammalian cells such as neurons (A). The loss of this mechanism leads to increase in aggregate levels resulting in stress (B).