Viral killer toxins induce caspase-mediated apoptosis in yeast

In yeast, apoptotic cell death can be triggered by various factors such as H2O2, cell aging, or acetic acid. Yeast caspase (Yca1p) and cellular reactive oxygen species (ROS) are key regulators of this process. Here, we show that moderate doses of three virally encoded killer toxins (K1, K28, and zygocin) induce an apoptotic yeast cell response, although all three toxins differ significantly in their primary killing mechanisms. In contrast, high toxin concentrations prevent the occurrence of an apoptotic cell response and rather cause necrotic, toxin-specific cell killing. Studies with Δyca1 and Δgsh1 deletion mutants indicate that ROS accumulation as well as the presence of yeast caspase 1 is needed for apoptosis in toxin-treated yeast cells. We conclude that in the natural environment of toxin-secreting killer yeasts, where toxin concentration is usually low, induction of apoptosis might play an important role in efficient toxin-mediated cell killing

Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1.

Hepatitis C virus (HCV) infection is closely tied to the lipid metabolism of liver cells. Here we identify the triglyceride-synthesizing enzyme diacylglycerol acyltransferase-1 (DGAT1) as a key host factor for HCV infection. DGAT1 interacts with the viral nucleocapsid core and is required for the trafficking of core to lipid droplets. Inhibition of DGAT1 activity or RNAi-mediated knockdown of DGAT1 severely impairs infectious virion production, implicating DGAT1 as a new target for antiviral therapy

Why yeast cells can undergo apoptosis: death in times of peace, love, and war

The purpose of apoptosis in multicellular organisms is obvious: single cells die for the benefit of the whole organism (for example, during tissue development or embryogenesis). Although apoptosis has also been shown in various microorganisms, the reason for this cell death program has remained unexplained. Recently published studies have now described yeast apoptosis during aging, mating, or exposure to killer toxins (Fabrizio, P., L. Battistella, R. Vardavas, C. Gattazzo, L.L. Liou, A. Diaspro, J.W. Dossen, E.B. Gralla, and V.D. Longo. 2004. J. Cell Biol. 166:1055–1067; Herker, E., H. Jungwirth, K.A. Lehmann, C. Maldener, K.U. Frohlich, S. Wissing, S. Buttner, M. Fehr, S. Sigrist, and F. Madeo. 2004. J. Cell Biol. 164:501–507, underscoring the evolutionary benefit of a cell suicide program in yeast and, thus, giving a unicellular organism causes to die for

Chronological aging leads to apoptosis in yeast

During the past years, yeast has been successfully established as a model to study mechanisms of apoptotic regulation. However, the beneficial effects of such a cell suicide program for a unicellular organism remained obscure. Here, we demonstrate that chronologically aged yeast cultures die exhibiting typical markers of apoptosis, accumulate oxygen radicals, and show caspase activation. Age-induced cell death is strongly delayed by overexpressing YAP1, a key transcriptional regulator in oxygen stress response. Disruption of apoptosis through deletion of yeast caspase YCA1 initially results in better survival of aged cultures. However, surviving cells lose the ability of regrowth, indicating that predamaged cells accumulate in the absence of apoptotic cell removal. Moreover, wild-type cells outlast yca1 disruptants in direct competition assays during long-term aging. We suggest that apoptosis in yeast confers a selective advantage for this unicellular organism, and demonstrate that old yeast cells release substances into the medium that stimulate survival of the clone

An AIF orthologue regulates apoptosis in yeast

Apoptosis-inducing factor (AIF), a key regulator of cell death, is essential for normal mammalian development and participates in pathological apoptosis. The proapoptotic nature of AIF and its mode of action are controversial. Here, we show that the yeast AIF homologue Ynr074cp controls yeast apoptosis. Similar to mammalian AIF, Ynr074cp is located in mitochondria and translocates to the nucleus of yeast cells in response to apoptotic stimuli. Purified Ynr074cp degrades yeast nuclei and plasmid DNA. YNR074C disruption rescues yeast cells from oxygen stress and delays age-induced apoptosis. Conversely, overexpression of Ynr074cp strongly stimulates apoptotic cell death induced by hydrogen peroxide and this effect is attenuated by disruption of cyclophilin A or the yeast caspase YCA1. We conclude that Ynr074cp is a cell death effector in yeast and rename it AIF-1 (Aif1p, gene AIF1)

Induction of autophagy by spermidine promotes longevity.

n/

Phosphatidylserine-exposing extracellular vesicles in body fluids are an innate defence against apoptotic mimicry viral pathogens

Some viruses are rarely transmitted orally or sexually despite their presence in saliva, breast milk, or semen. We previously identified that extracellular vesicles (EVs) in semen and saliva inhibit Zika virus infection. However, the antiviral spectrum and underlying mechanism remained unclear. Here we applied lipidomics and flow cytometry to show that these EVs expose phosphatidylserine (PS). By blocking PS receptors, targeted by Zika virus in the process of apoptotic mimicry, they interfere with viral attachment and entry. Consequently, physiological concentrations of EVs applied in vitro efficiently inhibited infection by apoptotic mimicry dengue, West Nile, Chikungunya, Ebola and vesicular stomatitis viruses, but not severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus 1, hepatitis C virus and herpesviruses that use other entry receptors. Our results identify the role of PS-rich EVs in body fluids in innate defence against infection via viral apoptotic mimicries, explaining why these viruses are primarily transmitted via PS-EV-deficient blood or blood-ingesting arthropods rather than direct human-to-human contact

Guidelines and Recommendations on Yeast Cell Death Nomenclature

Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death routines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the authors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the progress of this vibrant field of research

Guidelines and recommendations on yeast cell death nomenclature

Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cel-lular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the defi-nition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differ-ential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death rou-tines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the au-thors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the pro-gress of this vibrant field of research

Altruistic cell death and new ways of caspase-dependent apoptosis in Saccharomyces cerevisiae

In den letzten Jahren konnte der Einzeller Saccharomyces cerevisiae als Modellorganismus für apoptotische Prozesse etabliert werden. Im Rahmen dieser Arbeit wurde ein altruistischer Aspekt des apoptotischen Zelltodes der Hefe aufgeklärt. Im chronologischen Altern, also unter physiologischen Bedingungen, sterben die meisten Zellen einer klonalen Kultur mit den phänotypischen Markern der Apoptose. Dieser apoptotische Zelltod ist abhängig von der Hefecaspase Yca1p und reaktiven Sauerstoffspezies (ROS). Verhindert bzw. verzögert man aber den Zelltod im chronologischen Altern durch die Deletion der Hefecaspase Yca1p birgt dies auf lange Sicht Selektionsnachteile für die Population, denn gealterte Mutantenzellen sind im adaptiven Wachstum behindert. Außerdem überlebt der Wildtyp die Mutanten in einem kompetitiven Überlebensassay, hat also im direkten Vergleich langfristig Selektionsvorteile. Es konnte zudem gezeigt werden, dass alternde Hefezellen Substanzen sezernieren, die das Überleben von anderen alten Zellen fördern. Des Weiteren konnte die durch Lsm4p Mutation ausgelöste Apoptose mechanistisch näher charakterisiert werden. Da Lsm Proteine beim mRNA splicing und decapping involviert sind, wurde untersucht, welche von beiden Funktionen bei einer Fehlregulation Apoptose auslöst. Störungen im mRNA decapping durch Mutationen oder Disruptionen der beteiligten Proteine führen zu einem Zelltod, der mit den klassischen Marken der Apoptose einhergeht. Dieser Zelltod, nicht aber die mRNA Stoffwechselstörung kann durch die Disruption der Hefecaspase Yca1p verhindert werden.During the past years, yeast has been successfully established as a model organism to study mechanisms of apoptotic regulation. In this thesis an altruistic aspect of apoptotic cell death of yeast is elucidated. During chronological aging, which represents a physiological scenario, most yeast cells of a monoclonal culture die exhibiting the phenotypic markers of apoptotic cell death. Age-induced cell death is dependent on the yeast caspase Yca1p and ROS. Disruption of age-induced apoptosis through deletion of yeast caspase YCA1 is disadvantageous for the monoclonal population, due to the fact that aged mutant cells lose the ability of regrowth. Moreover wild type cells outlast yca1 disruptants in direct competition assays indicating an evolutional advantage for wild type cells. It could be also shown that old yeast cells release substances into the medium that stimulate survival of other old cells. In addition apoptosis induced by mutation of Lsm4p was characterized further in its mechanism. As Lsm proteins have functions in mRNA splicing and decapping mechanisms, it was analyzed which process can cause apoptotic cell death. Interferences of mRNA decapping through deletion or mutation of proteins involved in this process lead to cell death accompanied by the classical markers of apoptosis. This cell death but not the disturbances in mRNA metabolism are dependent on yeast caspase Yca1p