Positive and negative effects of MCA1 deletion on stress sensitivity and virulence

Abstract Metacaspases are cysteine proteases, found in every group of organisms except metazoa. They are structural orthologs of caspases, which orchestrate apoptosis in metazoa. Like caspases ( C ysteine-dependent ASP artate-directed prote ASES ), paracaspases, and orthocaspases, metacaspases are class C14 proteases, with a hemoglobinase fold and catalytic cysteine residue. However, metacaspases cleave after arginine or lysine instead of aspartate, leading some to call for metacaspases to be renamed. Furthermore, most metacaspases are activated by calcium, they do not target the same range of proteins as caspases, and they tend to cut target proteins multiple times rather than at a single, canonical site. The Candida albicans metacaspase, Mca1p mediates cell death in response to various stresses but also possesses pro-life functions such as clearing protein aggregates and lifespan extension. Many plant and protist metacaspases lack cell death roles and mediate development, differentiation and immunity. This article highlights a reversed effect of Mca1p on growth inhibition by acetic acid, hydrogen peroxide and amphotericin B and on virulence of C. albicans , when injected into Galleria mellonella (wax moth) larvae, depending on whether cells originate from exponential or stationary phase culture. This reversal of metacaspase function hints at the protein’s dual nature and at the conditions that drive the switch from its pro-survival to its pro-death role.