Abstract
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.
Highlights
Cathepsin D (CatD) seems to have a pleiotropic role with respect to programmed cell death (PCD)
Pep4p is an essential player in the S. cerevisiae vacuolar proteolytic system, where it is important for both protein degradation and maturation of several vacuolar hydrolases.[23,24]
Combining clonogenic survival tests and the measurement of characteristic cell death markers, we show that the proteolytically inactive N-terminal propeptide of the yeast CatD ortholog (Pep4p) suppresses necrosis in a genetically regulated manner, arguing for the involvement of a cell death type known as ‘programmed necrosis’
Summary
CatD seems to have a pleiotropic role with respect to programmed cell death (PCD). ‘programmed necrosis’ represents (besides apoptosis) a further PCD subroutine present in yeast.[10,11]. Driven by the aforementioned considerations, we decided to investigate the role of Pep4p ( called yeast proteinase A), the yeast CatD ortholog,[23] on yeast aging and cell death. Using chronological aging as a means to physiologically induce necrotic cell death, we show that prolonged overexpression of Pep4p promotes survival by . We demonstrate that PEP4 deletion exacerbates both apoptosis and necrosis during chronological aging. Suppression of apoptosis by Pep4p relies on its proteolytic activity, whereas the repression of necrosis is mediated by the proteolytically inactive Pep4p propeptide, which promotes survival via a novel pathway, the stimulation of spermidine biosynthesis
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