The lysosomal endoprotease cathepsin D (CatD) is an essential player in general protein turnover and specific peptide processing. CatD-deficiency is associated with neurodegenerative diseases, whereas elevated CatD levels correlate with tumor malignancy and cancer cell survival. Here, we show that the CatD ortholog of the budding yeast Saccharomyces cerevisiae (Pep4p) harbors a dual cytoprotective function, composed of an anti-apoptotic part, conferred by its proteolytic capacity, and an anti-necrotic part, which resides in the protein's proteolytically inactive propeptide. Thus, deletion of PEP4 resulted in both apoptotic and necrotic cell death during chronological aging. Conversely, prolonged overexpression of Pep4p extended chronological lifespan specifically through the protein's anti-necrotic function. This function, which triggered histone hypoacetylation, was dependent on polyamine biosynthesis and was exerted via enhanced intracellular levels of putrescine, spermidine and its precursor S-adenosyl-methionine. Altogether, these data discriminate two pro-survival functions of yeast CatD and provide first insight into the physiological regulation of programmed necrosis in yeast.

Caspases are cysteine proteases that cleave their substrates after an aspartate residue. Besides their multiple vital roles ranging from immune regulation to spermatogenesis, they are crucial in most cell death pathways, representing a sort of executing sword in the hands of apoptosis. In 2000, a psi-Blast in-silico approach led Uren et al. 1 to identify two novel caspase-related families: metacaspases and paracaspases. Paracaspases are involved in the development of MALT lymphoma, but not in cell death execution, and are found both in eukaryotes owning caspases (animals), as well as in organisms lacking caspases. Metacaspases, on the other hand, are found only in eukaryotes that are devoid of caspases, for example, plants, protists and fungi. Similar to caspases, they contain a caspase-specific catalytic diad of histidine and cysteine, as well as a caspase-like secondary structure.Our lab was among the first to perform experiments on metacaspases showing that the sole metacaspase encoded by the genome of Saccharomyces cerevisiae (which we termed YCA1) is involved in oxidative stress-induced cell death. 2 Overexpression of YCA1 caused a type of cell death that was accompanied by apoptotic markers, while deletion of YCA1 protected against apoptosis caused by reactive oxygen species or chronological aging. 2 We thus had revealed that one metacaspase, YCA1, was involved in the same process as caspases, namely programmed cell death (PCD). Indeed, many groups subsequently unfolded the crucial contribution of metacaspases to cell death execution upon various stresses in yeast and other fungi, 3-6 as well as in plants. 7 Bozhkov, Zhivotovsky and colleagues 8 could even demonstrate that the plant metacaspase mcII-Pa shapes the embryo of Norway spruce (Picea abies) during development, presumably through its implication in developmental cell death. Together with the unequivocal fact of a common evolutionary origin, these results made us conclude that, in functional terms, metacaspases behave like caspases, thus unchaining a stormy scientific debate.Driven by the fact that caspases occur in animals but metacaspases are present in all kingdoms except animals, many authors deduced that, although cell death is a universal and fundamental process, the implication of caspases in lethal processes is not necessarily conserved. The discovery that metacaspases have a different cleavage specificity than caspases -they hydrolyze proteins after arginine or lysine (basic residues), not after aspartate (an acidic residue) 7,9 -added further fuel to the discussion. In fact, the exclusion of metacaspases from the caspase family and their regrouping into a separate family in the CD clan of cysteine peptidases was demanded. 10 In other words, it was implicated that metacaspases are not caspases. Nevertheless, we strongly felt that Yca1p, a protein that possesses sequence homology to human caspases, and the knockout of which rescues roughly 40% of all cell death scenarios tested in yeast, should retain the name 'metacaspase'. Nomenclature re...