Viruses activate a genetically conserved cell death pathway in a unicellular organism

Abstract

Given the importance of apoptosis in the pathogenesis of virus infections in mammals, we investigated the possibility that unicellular organisms also respond to viral pathogens by activating programmed cell death. The M1 and M2 killer viruses of Saccharomyces cerevisiae encode pore-forming toxins that were assumed to kill uninfected yeast cells by a nonprogrammed assault. However, we found that yeast persistently infected with these killer viruses induce a programmed suicide pathway in uninfected (nonself) yeast. The M1 virus–encoded K1 toxin is primarily but not solely responsible for triggering the death pathway. Cell death is mediated by the mitochondrial fission factor Dnm1/Drp1, the K+ channel Tok1, and the yeast metacaspase Yca1/Mca1 encoded by the target cell and conserved in mammals. In contrast, cell death is inhibited by yeast Fis1, a pore-forming outer mitochondrial membrane protein. This virus–host relationship in yeast resembles that of pathogenic human viruses that persist in their infected host cells but trigger programmed death of uninfected cells.

Mitochondrial factors with dual roles in death and survival

“…On the other hand, if programmed cell death did not arise until multicellular organisms appeared during evolution, as is commonly thought, then the pro-death function Drp1/ Dnm1 presumably would not be preserved in yeast. To the contrary, yeast Drp1/Dnm1 also promotes programmed cell death in yeast Ivanovska and Hardwick, 2005). Similarly, the yeast homologue of AIF promotes cell death in yeast (Vahsen et al, 2004;Wissing et al, 2004).…”

“…The M1 killer virus triggers cell death that is mediated by the mitochondrial fission factor Dnm1/Drp1, the K þ channel Tok1, and in part by the metacaspase Mca1/Yca1 genes encoded by the target cell (Ivanovska and Hardwick, 2005;Reiter et al, 2005). This virus-host relationship in yeast resembles that of pathogenic human viruses that persist in their infected host cells but trigger programmed cell death of uninfected cells (e.g., HIV).…”

Metacaspase-8 Modulates Programmed Cell Death Induced by Ultraviolet Light and H2O2 in Arabidopsis

“…In addition, different PCD pathways activated in plants may be either metacaspase-dependent or metacaspase-independent. This hypothesis is exemplified in yeast, where the single yeast metacaspase (YCA1) mediates PCD induced by H 2 O 2 or acetic acid (5), by viruses (17), and by hyperosmotic stress (18), but in contrast, it is not required for PCD during mating (19), triggered by ammonia (20), or induced by Bax expression (21). We show here that Arabidopsis metacaspase-8, a type II metacaspase, is up-regulated by the oxidative stress caused by UVC and leading to PCD, and this up-regulation is RCD1-dependent.…”

Alternate functions of viral regulators of cell death

“…This observation caused us to reconsider other observations in our lab, such as newly established human Bcl-2-and Bcl-x Lexpressing cell lines that exhibit growth-inhibited phenotypes in the first week of selection compared to matched controls, but lose this slow-growth phenotype thereafter (DG Kirsch and JM Hardwick, unpublished). 6,63,99 Newly established cell lines expressing protease-resistant murine Bad, a BH3-only protein, readily reveals the antideath function of Bad, but only for the first several passages. This antideath function of Bad was gradually lost relative to matched controls over the next few weeks, but was repeatedly recovered by generating new cell lines (SY Seo and JM Hardwick, unpublished).…”

“…[1][2][3][4] In multicellular organisms, and in colonies of single-cell species, the activation of cell suicide in response to a virus infection is thought to have arisen during evolution as an effective early defense strategy to prevent the spread of infection. 5,6 This ancient altruistic suicide mechanism of infected cells is a crucial component of the innate host response.…”