Autophagy and cell death in model organisms

Abstract

Autophagy evolved in unicellular eukaryotes as a means for surviving nutrient stress. During the course of evolution, as multicellular organisms developed specialized cell types and complex intracellular signalling networks, autophagy has been summoned to serve additional cellular functions. Numerous recent studies indicate that apart from its pro-survival role under nutrient limitation, autophagy also participates in cell death. However, the precise role of this catabolic process in dying cells is not fully understood. Although in certain situations autophagy has a protective function, in other types of cell death it actually contributes to cellular destruction. Simple model organisms ranging from the unicellular Saccharomyces cerevisiae to the soil amoeba Dictyostelium discoideum and the metazoans Caenorhabditis elegans and Drosophila melanogaster provide clearly defined cell death paradigms that can be used to dissect the involvement of autophagy in cell death, at the molecular level. In this review, we survey current research in simple organisms, linking autophagy to cell death and discuss the complex interplay between autophagy, cell survival and cell death. Autophagy is a self-degradation process that is essential for survival, differentiation, development, and homeostasis. There are at least three forms of autophagy -chaperonemediated autophagy, microautophagy, and macroautophagy -that differ with respect to their mechanisms, physiological functions and cargo specificity. In the best-studied form of autophagy, macroautophagy (herein referred to as autophagy), parts of the cytoplasm, long-lived proteins and intracellular organelles are sequestered within cytoplasmic double-membrane vesicles called autophagosomes or autophagic vacuoles. These characteristic vacuoles are finally delivered to lysosomes for bulk degradation (Figure 1).Autophagy was discovered in mammalian cells and has been extensively investigated in yeast. 1 These studies have identified many genes encoding proteins involved in autophagy (ATG proteins). 2 ATG proteins participate in the induction of autophagy, the formation, expansion and maturation of autophagosomes, and in the retrieval of autophagic proteins from mature autophagosomes. 3 Fusion processes occur through the t-and v-SNARE complexes, and other molecules, such as the Rab GTPases and components of the vacuolar protein-sorting (VPS) complex. Several protein kinases regulate autophagy, the best characterized being the mammalian target of rapamycin (mTOR), which negatively regulates the pathway. 4 Downstream of TOR kinase, numerous proteins encoded by ATG genes (more than 20 genes in yeast) are essential for the execution of autophagy. 5 The autophagic process is evolutionarily conserved and most yeast ATG genes have homologues in higher organisms (Table 1).Autophagy has also been linked to cell death pathways. Indeed, excess cytoplasmic vacuolation is the main feature of type II programmed cell death or autophagic cell death. Both protective and destructive contributions of autop...

Neutrophil extracellular trap cell death requires both autophagy and superoxide generation

“…We hypothesized that the numerous vesicles might originate from induction of autophagy because many cell types exhibit massive vacuolization during autophagy-associated cell death [27,28]. In agreement with the massive vacuolization on PMA stimulation, which was observed by live cell imaging ( Figure 1; Supplementary information, Video S1), transmission electron microscopic analysis of neutrophils revealed the presence of vesicles with double membranes ( Figure 3A).…”

“…Bacterial challenge is known to induce Nox2 activation [27], but it can also induce autophagy [35,36]. It was recently shown that engagement of Toll-like receptor and Fc receptor signaling during phagocytosis induces autophagy in primary neutrophils [36].…”

Autophagy and ageing: Insights from invertebrate model organisms

“…Autophagy is also triggered as an adaptive response to a broad range of other extracellular or intracellular stressors such as hypoxia, heat, reactive oxygen species (ROS) and accumulation of damaged cytoplasmic components (Levine and Klionsky, 2004). Suppression of autophagy by knockout or knockdown of essential autophagy genes triggers apoptosis or necrosis in cells that would otherwise survive under stress conditions (reviewed in Kourtis and Tavernarakis, 2009;Mathew et al, 2009).…”

“…Excessive autophagy induced by extreme conditions, such as toxins and necrosis-triggering insults, might cause uncontrollable degradation or sequestration of cells contents into autophagosomes resulting in undesirable cell death if not properly regulated (reviewed in Kourtis and Tavernarakis, 2009;Yang and Klionsky, 2010).…”

Toward the understanding of autophagy regulation and its interplay with cell death pathways

“…In the first issue of 2009, Cell Death and Differentiation has already published nine reviews on the topic of autophagy in aging, disease and death. [1][2][3][4][5][6][7][8][9] These are now followed by another six papers covering more specific aspects of the complex regulation of this process and its crosstalk with apoptosis and other essential cellular functions, such as energy production, vesicular traffic and cellular immunity. [10][11][12][13][14][15] Three reviews focus on the molecular mechanisms regulating the induction, formation and maturation of the autophagosome vesicles.…”