Apoptosis in yeast

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Apoptosis is a highly regulated cellular suicide program crucial for metazoan development. However, dysfunction of apoptosis also leads to several diseases. Yeast undergoes apoptosis after application of acetic acid, sugar- or salt-stress, plant antifungal peptides, or hydrogen peroxide. Oxygen radicals seem to be key elements of apoptotic execution, conserved during evolution. Furthermore, several yeast orthologues of central metazoan apoptotic regulators have been identified, such as a caspase and a caspase-regulating serine protease. In addition, physiological occurrence of cell death has been detected during aging and mating in yeast. The finding of apoptosis in yeast, other fungi and parasites is not only of great medical relevance but will also help to understand some of the still unknown molecular mechanisms at the core of apoptotic execution.

Introduction

Saccharomyces cerevisiae has been successfully used as a model for complex physiological processes of metazoan cells. Fundamental results have been achieved in the fields of aging, vesicular transport or cell division.

Until a few years ago, apoptotic cell death seemed to be a process that was absent in yeast. Not only did a cellular suicide program make no sense for an organism consisting of just one cell, plain homology searches indicated the absence of crucial regulators of apoptosis. Therefore, the discovery of an apoptotic phenotype in a yeast strain carrying a CDC48 mutation [1] was unexpected. Like mammalian cells, yeast cells undergo apoptosis showing characteristic markers: DNA cleavage and apoptosis-typical chromatin condensation (margination), externalization of phosphatidylserine to the outer leaflet of the plasma membrane [1] and cytochrome c release from mitochondria 2., 3.•. The characterization of ROS (reactive oxygen species) acting as central regulators of yeast apoptosis confirmed that the similarity to the metazoan process is not restricted to the appearance of a phenotype [4]. The discovery of several yeast orthologues of crucial apoptotic regulators in recent years provided the final proof that yeast and metazoan apoptosis are two versions of the same cellular program (Figure 1). In particular, the finding of a caspase [5••], the apoptotic serine protease HtrA2/Omi [6••], the transkingdom Bax inhibitor BI-1 [7], conserved proteasomal pathways (such as Cdc6 destruction) 8.••, 9., and physiological death scenarios during aging in yeast 10., 11.• finally established this unique model organism as a tool for apoptosis research. Even for the yeast Cdc48 protein, which has led to the first discovery of yeast apoptosis, an human orthologue has since been confirmed as a regulator of mammalian apoptosis, having antiapoptotic functions [12], which are particularly apparent during neuronal pathology [13]. Even the question of why it would make sense for a single-celled organism to undergo suicide has been answered: it might be a mechanism of sparing nutrient resources for the fittest individuals in stressful times [11].

In this review, we focus on the most recent key works in the rapidly growing field of apoptosis in yeast.

Section snippets

Drug-induced yeast apoptosis

Several substances have been used to induce yeast apoptosis in wild type cells, most commonly, low doses of H2O2 or acetic acid 4., 14.. Aspirin [15] triggers yeast apoptosis in dependency of the carbon source. Osmotin is a plant peptide that triggers apoptosis as a form of plant defense against pathogenic fungi [16]. Yeast cells that are exposed to salt (NaCl) show cell death accompanied by nuclear markers of apoptosis and can be rescued by expression of Bcl-2 [17] or deletion of yeast caspase

Conserved regulators of apoptosis: metacaspases and serine proteases

The discrepancy between the apparent absence of apoptotic genes and the occurrence of an apoptotic phenotype in yeast was solved with the discoveries of the caspase orthologue Yca1 [5••] and the serine protease HtrA2/Omi [6••], a classical regulator of caspase activity in metazoan cells 35., 36..

Disruption of YCA1 reduces cell death and formation of an apoptotic phenotype in response to oxygen stress or aging [5••]. Overexpression of the gene does not induce apoptosis per se, but increases the

The physiology of yeast apoptosis: a reason to die for

Cellular aging provides a natural scenario in which apoptosis might be of advantage for the clone. Two forms of aging have been described in yeast, both of which are reflected in the aging processes of mammalian cells.

Yeast replicative life-span is defined as the number of divisions an individual cell undergoes before dying [50]. Replicative old cells die showing an accumulation of ROS and exhibiting characteristic apoptotic phenotypes [10]. Yeast chronological life-span is the length of time a

Other fungi and protists of clinical relevance

Research into yeast apoptosis not only serves as a model for higher eukaryotes, but has also revealed a sensitive spot to fight unicellular eukaryotic pathogens.

New antifungal agents are urgently required to combat life-threatening infections that are caused by opportunistic fungal pathogens like Candida albicans, Aspergillus nidulans or fumigatus. The manipulation of endogenous fungal PCD responses might provide a basis for future therapies.

Sphingosines have recently been shown to induce

Conclusions and perspectives

Mounting evidence suggests a common evolutionary origin for the cell death processes of metazoans and other eukaryotes, with a conservation of the basal apoptotic key players between mammals and yeast. The yeast model is now established enough to take the next step. Taking the existence of known apoptotic executioners such as caspases or caspase-regulating serine proteases, yeast might now help to unravel the highly complicated hierarchy between different apoptotic pathways and, by extension,

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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