Regulation of autophagy in mammals and its interplay with apoptosis

A growing number of publications show that apoptosis induction is often associated with increased autophagy indicating the existence of an interplay between these two important cellular events. The simultaneous activation of both phenomena has been detected not only in experimental settings but also in vivo under physiological and pathological conditions. Despite these studies, the reciprocal influence of the two pathways in vivo has still not been completely understood. It is clear that autophagy and apoptosis are strictly interconnected, as highlighted by the finding that the two pathways share key molecular regulators. Many novel aspects of the crosstalk between apoptosis and autophagy have recently emerged showing how complex is this relationship and how critical is for the overall fate of the cell. In this mini-review we will focus on some key experiments trying to decipher as to whether autophagy contributes to apoptosis modulation in vivo.     

Ambra1 regulates autophagy and development of the nervous system

Autophagy is a self-degradative process involved both in basal turnover of cellular components and in response to nutrient starvation or organelle damage in a wide range of eukaryotes. During autophagy, portions of the cytoplasm are sequestered by double-membraned vesicles called autophagosomes, and are degraded after fusion with lysosomes for subsequent recycling. In vertebrates, this process acts as a pro-survival or pro-death mechanism in different physiological and pathological conditions, such as neurodegeneration and cancer; however, the roles of autophagy during embryonic development are still largely uncharacterized. Beclin1 (Becn1; coiled-coil, myosin-like BCL2-interacting protein) is a principal regulator in autophagosome formation, and its deficiency results in early embryonic lethality. Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy, as revealed by its overexpression and by RNA interference experiments in vitro. Notably, Ambra1 functional deficiency in mouse embryos leads to severe neural tube defects associated with autophagy impairment, accumulation of ubiquitinated proteins, unbalanced cell proliferation and excessive apoptotic cell death. In addition to identifying a new and essential element regulating the autophagy programme, our results provide in vivo evidence supporting the existence of a complex interplay between autophagy, cell growth and cell death required for neural development in mammals.