Academic journal article Genetics

Programmed Cell Death Initiation and Execution in Budding Yeast

Academic journal article Genetics

Programmed Cell Death Initiation and Execution in Budding Yeast

Article excerpt

TWO types of regulated cell death, necrosis and programmed cell death, have been described in budding yeast (Lin and Austriaco 2014). Necrotic cell death was originally characterized as a simple collapse of the cell leading to cell wall breakdown and ultimately lysis. However, more recent studies report the existence of a regulatory network governing necrotic cell death (Eisenberg et al. 2010). This review concentrates on programmed cell death (PCD) in yeast, which closely resembles the intrinsic or mitochondrial-derived apoptosis in multicellular organisms (Perrone et al. 2008). Mammalian apoptosis is initiated by accumulation of Bcl2 homology 3 (BH3) containing proteins such as Bax on the mitochondrial outer membrane. Bax induces pore formation leading to the release of cytochrome c,whichstimulates a cascade of proteases termed c ysteine-dependent aspartate-specificproteases or caspases (Danial and Korsmeyer 2004). Plants and fungi possess a related protease family called metacaspases (Uren et al. 2000). Metacaspases share sequence and functional similarities but differ with respect to substrate recognition sites (asparagine/lysine rather than aspartic acid). Budding yeast possesses a single metacaspase (Yca1) and BH3 domain protein (Ybh3), which are both required for oxidative stress-induced PCD. Standard assays for PCD, such as double strand breaks or phophatidylserine externalization (Annexin V staining), routinely used to monitor apoptosis in metazoans, are also employed to assay PCD in yeast (Madeo et al. 1997). However, following excessive damage, these PCD hallmarks may be joined by necrotic markers (e.g., propidium iodide permeability) (Yamaki et al. 2001). Therefore, it is important to note that these different cell-death modes can be observed simultaneously within a population and care should be used when judging the contribution that each death pathway has on overall cell viability.

Oxidative Stress, a Common Denominator for PCD Initiation

There are many stimuli, either externally or internally derived, able to induce PCD in yeast. For example, aging (Corte-Real and Madeo 2013), extreme pH environment (Ludovico et al. 2001), plant toxins (Narasimhan et al. 2001), defects in actin function (Gourlay and Ayscough 2006), osmotic stress (Silva et al. 2005), acetic acid (Ludovico et al. 2002), the presence of lipid hydroperoxides (Alic et al. 2003), and prolonged mating-factor exposure (Severin and Hyman 2002) (although the exact nature of this cell death is in question) (Zhang et al. 2006) all stimulate PCD. Although these stressors appear different, many have in common the ability to generate internal reactive oxygen species (ROS). For example, a specificmutationinCdc48 induces PCD in yeast (Madeo et al. 1997) due to elevated ROS (Madeo et al. 1999) produced from defective mitochondria (Braun et al. 2006; Braun and Zischka 2008). Similarly, defects in endoplasmic reticulum (ER)-dependent protein folding also produces ROS (Tu and Weissman 2004) to levels sufficient to induce PCD (Haynes et al. 2004). In addition, defects in the electron transport chain (ETC) lead to ER-produced ROS through hyperactivation of the ER NADPH oxidase Yno1 (Leadsham et al. 2013). These findings demonstrate the intricate relationships that have evolved between organelles that produce and respond to ROS-induced damage. The transcriptional response to, and the macromolecular damage caused by, oxidative stress in yeast are the subject of several excellent reviews (Avery 2011; Farrugia and Balzan 2012; Morano et al. 2012) and will not be detailed here. Rather, given the universal nature of the oxidative stress response from yeast to humans, this review focuses on recent insights into the signaling systems that transduce the ROS signal and the effector proteins that coordinate the response between organelles in budding yeast.

External origins of ROS

The cell maintains redox homeostasis by balancing low-level ROS produced by organelles or exogenous sources with an arsenal of antioxidant enzymes that neutralize reactive oxygen (e. …

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