The ferritin sub-family of iron binding proteins form multi-subunit nanotype iron-storage cages that serve to store iron and prevent iron toxicity. Of importance ferritin can prevent cell death in mammalian cells in response to many apoptotic stresses such as hydrogen peroxide. Here we describe the identification of human H-ferritin as a suppressor of the pro-apoptotic murine Bax sequence in yeast. Using a combination of spot and vital dye-based assays, we demonstrate that ferritin is a general pro-survival sequence since it also prevents the effects other stresses including copper and rapamycin in yeast. Although ferritins are phylogenetically widely distributed and are present in most species of Eukarya, Bacteria and Archaea, ferritin is conspicuously absent in most fungal species including Saccharomyces cerevisiae. Our observation that heterologous human H-ferritin retains pro-survival functions when expressed in yeast indicates either ferritin is self-functioning or that yeast has a yet to be uncovered ferritin. To address the later possibility, we carried out a detailed in silico analysis of the yeast proteome leading to the identification of a protein of unknown function to be a strong candidate for the elusive yeast ferritin (yFer1). In addition to sharing 20% sequence identity with the 183 residue human H-ferritin, yFer1 also has similar functional properties as ferritin when overexpressed in yeast including preventing the effects of Bax and copper. The study of pro-survival sequences offers information not only on the function of pro-apoptotic sequences but also on the nature of the different forms and sub-forms of PCD. For example, copper and rapamycin likely induce similar forms of apoptotic-like PCD given that their lethal effects can be prevented by the overexpression of the same anti-apoptotic sequences including human ferritin and the putative yeast ferritin. In contrast we find that cell death induced by iron is distinctly different in part because it can only be prevented by a small subset of pro-survival proteins including the newly identified putative yeast ferritin. A detailed comparison of the copper and iron mediated PCD subroutines, including potential areas of cross-talk are under investigation and will be discussed in more detail.
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Expression of human H ferritin prompts the identification of a hitherto elusive yeast orthologue and enables parsing of distinct iron-induced cell death pathways in Saccharomyces cerevisiae
Published: 15 October 2015 by MDPI in 1st Electronic Conference on Molecular Science session Importance of Cell Death Pathways in Biology
Keywords: yeast; anti-apoptosis; necroptosis; apoptosis; ferritin