Meiotic viral attenuation through an ancestral apoptotic pathway

Abstract

The programmed release of apoptogenic proteins from mitochondria is a core event of apoptosis, although ancestral roles of this phenomenon are not known. In mammals, one such apoptogenic protein is Endonuclease G (EndoG), a conserved mitochondrial nuclease that fragments the DNA of dying cells. In this work, we show that budding yeast executes meiotically programmed mitochondrial release of an EndoG homolog, Nuc1, during sporulation. In contrast to EndoG’s ostensible pro-death function during apoptosis, Nuc1 mitochondrial release is pro-survival, attenuating the cytosolic L-A and Killer double-stranded RNA mycoviruses and protecting meiotic progeny from the catastrophic consequences of their derepression. The protective viral attenuation role of this pathway illuminates a primordial role for mitochondrial release of EndoG, and perhaps of apoptosis itself.

Viral attenuation by Endonuclease G during yeast gametogenesis: insights into ancestral roles of programmed cell death?

“…This observation is consistent with the hypothesis that mitochondrially-released Nuc1 during yeast meiotic PCD accomplishes nucleosomal laddering, paralleling the role of mitochondrial membrane permeabilization in the release of apoptogenic proteins during mammalian PCD [9]. We recently confirmed that Nuc1 accumulates in the cytosol of meiotic cells in a developmentally programmed manner, supporting this model [10].…”

“…Open questions remain concerning the mechanistic basis and developmental regulation of Nuc1's dual roles in viral attenuation and meiotic PCD. Although Nuc1 enzymatic activity is required for attenuation, there is only circumstantial evidence for direct attenuation of Killer by cytosolic Nuc1 [10]. Indeed, Liu and Dieckmann identified L-A attenuation by Nuc1 in vegetative haploid cells, whereas we did not detect Nuc1 in the cytosol of vegetative cells [16].…”

“…Our recent study presents evidence that highlights viruses as targets of Nuc1 during meiotic PCD [10]. Indeed, the host-virus arms race is a ubiquitous feature of life and has been proposed to underlie the evolution of PCD [13].…”

“…We found that NUC1 is essential for viral attenuation of M in parallel to SkiC during sporulation. Mutant spores lacking both NUC1 and SKI3 exhibited lethality due to massive intracellular accumulation of Killer toxin [10]. Killer toxin is secreted via the secretory pathway in vegetative cells, and the secretory pathway is re-routed inwards to accomplish pro-spore membrane biogenesis during sporulation [3].…”

“…Thus, we posited that VDACs facilitate meiotically programmed relocation of Nuc1 to the cytosol. This population of Nuc1 consequently contributes to Killer attenuation, perhaps by targeting M (and/or L-A) RNA for digestion [10].…”