Caspases, a family of conserved proteases, are required for apoptosis in all metazoans but play roles in processes other than apoptosis; however, the molecular mechanisms and physiological functions of many of these 'non-canonical roles' remain largely unknown. Most of the cells that are fated to die through apoptosis during C. elegans development are the smaller daughter of a 'mother' cell that divides asymmetrically by size and fate. In a recent study, we reported that the loss of C. elegans
ced-3caspase compromises the asymmetric division of such mother cells and causes the daughters fated to die to increase in size. Thus, we uncovered a novel non-canonical role of
ced-3caspase in asymmetric cell division (Mishra et al., 2018). To elucidate the molecular mechanism through which
ced-3caspase promotes asymmetric cell division, we screened for physical interactors of CED-3 protein and identified the conserved RhoGEF ECT-2. ECT-2 activates the small GTPase RHO-1 and thereby promotes contractility of the actomyosin network. Our genetic data suggests that
ced-3 caspase acts upstream of ect-2RhoGEF in mother cells to promote daughter cell size asymmetry. We also provide evidence that prior to metaphase, ECT-2RhoGEF is asymmetrically localised in mother cells, and that this is dependent on
ced-3caspase. Thus, we hypothesize that CED-3caspase promotes local activation of ECT-2RhoGEF, thereby allowing asymmetric cortical contractility, which is necessary for unequal mother cell division. Finally, it has previously been reported that increasing the size of cells fated to die compromises the ability of these cells to undergo apoptosis. We now demonstrate that, conversely, decreasing the size of cells fated to die promotes their ability to undergo apoptosis and suppresses the cell death abnormal (Ced) phenotype caused by partial
ced-3caspase loss-of-function mutations but not a putative
ced-3caspase null mutation. Based on these observations, we propose that the non-canonical role of
ced-3caspase in asymmetric mother cell division ensures that the sizes of cells fated to die are below a critical 'lethal' size, necessary for efficient apoptosis execution. Hence, we have discovered reciprocal interactions between the apoptosis pathway and cell size in the context of apoptotic cell death during C. elegans development. References: Mishra, N., Wei, H. & Conradt, B. Caenorhabditis elegans
ced-3 Caspase Is Required for Asymmetric Divisions That Generate Cells Programmed To Die. Genetics 210, 983-998 (2018).