Human initiator caspases trigger apoptotic and autophagic phenotypes in Saccharomyces cerevisiae

Caspases are a family of proteases that participate in the progression and execution of the apoptotic program. However, regulation of the caspase activation and their substrates has not yet been fully elucidated. Here we explore the effect of the ectopic expression of the human initiator caspases-8 and -10 in Saccharomyces cerevisiae. Our results showed that the expression of human CASP10 and CASP8 triggers certain apoptotic markers such as a massive production of reactive oxygen species (ROS), chromatin condensation and phosphatidylserine externalization, finally leading to cell death. In response to hydroxyurea (HU), yeast cells expressing caspase-10 did not reduce the replication of DNA and escaped to the intra-S checkpoint of the cell cycle. In addition, caspase-10 expression induced yeast vacuolization and a vacuole-associated phenotype resembling autophagy. Other intracellular alterations such as disorganization of the actin cytoskeleton, cell wall damage, and aberrations within the endoplasmic reticulum lumen were also associated with caspase-10 expression. Furthermore, caspase-induced cell death was completely dependent on the proteolytic activation of the enzyme but, in contrast, was not dependent on either of the endogenous yeast apoptotic proteins Aif1 and Mca1 or the mitochondria. © 2008 Elsevier B.V.This work was supported by grants from Ministerio de Ciencia e Innovación of Spain (AGL2005-07245-C03-03 to J. L. R., and SAF2008-02251 and RD06/0020/1037 - Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III to F. M.), Junta de Castilla y León (SA008B08) to A. J. Fundación “la Caixa” (BM05-30-0) and NIH grant GM621284 to A. M. N.. P. L. S. and A. C. M. are recipients of FPU predoctoral fellowships from the Spanish Ministerio de Educación y Ciencia.Peer Reviewe