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...

Ageing is driven by the inexorable and stochastic accumulation of damage in biomolecules vital for proper cellular function. Although this process is fundamentally haphazard and uncontrollable, senescent decline and ageing is broadly influenced by genetic and extrinsic factors. Numerous gene mutations and treatments have been shown to extend the lifespan of diverse organisms ranging from the unicellular Saccharomyces cerevisiae to primates. It is becoming increasingly apparent that most such interventions ultimately interface with cellular stress response mechanisms, suggesting that longevity is intimately related to the ability of the organism to effectively cope with both intrinsic and extrinsic stress. Here, we survey the molecular mechanisms that link ageing to main stress response pathways, and mediate age-related changes in the effectiveness of the response to stress. We also discuss how each pathway contributes to modulate the ageing process. A better understanding of the dynamics and reciprocal interplay between stress responses and ageing is critical for the development of novel therapeutic strategies that exploit endogenous stress combat pathways against age-associated pathologies.

Protein homeostasis (proteostasis) is one of the nodal points that need to be preserved to retain physiologic cellular/organismal balance. The ubiquitin‐proteasome system (UPS) is responsible for the removal of both normal and damaged proteins, with the proteasome being the downstream effector. The proteasome is the major cellular protease with progressive impairment of function during aging and senescence. Despite the documented age‐retarding properties of proteasome activation in various cellular models, simultaneous enhancement of the 20S core proteasome content, assembly, and function have never been reported in any multicellular organism. Consequently, the possible effects of the core proteasome modulation on organismal life span are elusive. In this study, we have achieved activation of the 20S proteasome at organismal level. We demonstrate enhancement of proteasome levels, assembly, and activity in the nematode Caenorhabditis elegans, resulting in life span extension and increased resistance to stress. We also provide evidence that the observed life span extension is dependent on the transcriptional activity of Dauer formation abnormal/Forkhead box class O (DAF‐16/FOXO), skinhead‐1 (SKN‐1), and heat shock factor‐1 (HSF‐1) factors through regulation of downstream longevity genes. We further show that the reported beneficial effects are not ubiquitous but they are dependent on the genetic context Finally, we provide evidence that proteasome core activation might be a potential strategy to minimize protein homeostasis deficiencies underlying aggregation‐related diseases, such as Alzheimer's disease (AD) or Huntington's disease (HD). In summary, this is the first report demonstrating that 20S core proteasome up‐regulation in terms of both content and activity is feasible in a multicellular eukaryotic organism and that in turn this modulation promotes extension of organismal health span and life span.—Chondrogianni, N., Georgila, K., Kourtis, N., Tavernarakis, N., Gonos, E. S. 20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans. FASEB J. 29, 611‐622 (2015). http://www.fasebj.org

Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has been evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7 α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FBXW7α results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7α is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7α deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer.

Heat stroke is a life-threatening condition, characterized by catastrophic collapse of thermoregulation and extreme hyperthermia. In recent years, intensification of heat waves has caused a surge of heat-stroke fatalities. The mechanisms underlying heat-related pathology are poorly understood. Here we show that heat stroke triggers pervasive necrotic cell death and neurodegeneration in Caenorhabditis elegans. Preconditioning of animals at a mildly elevated temperature strongly protects from heat-induced necrosis. The heat-shock transcription factor HSF-1 and the small heat-shock protein HSP-16.1 mediate cytoprotection by preconditioning. HSP-16.1 localizes to the Golgi, where it functions with the Ca(2+)- and Mn(2+)-transporting ATPase PMR-1 to maintain Ca(2+) homeostasis under heat stroke. Preconditioning also suppresses cell death inflicted by diverse insults, and protects mammalian neurons from heat cytotoxicity. These findings reveal an evolutionarily conserved mechanism that defends against diverse necrotic stimuli, and may be relevant to heat stroke and other pathological conditions involving necrosis in humans.