Compartmentalized regulation of autophagy regulators: fine-tuning AMBRA1 by Bcl-2.

Members of the anti-apoptotic Bcl-2 family and AMBRA1 (activating molecule in beclin 1-regulated autophagy) interact with Beclin 1 and control autophagy. Bcl-2 is a negative regulator of autophagy whereas AMBRA1 stimulates autophagy. A paper in this issue of The EMBO Journal reveals an interaction between AMBRA1 and Bcl-2 at the mitochondrial outer membrane. In response to nutrient withdrawal, this interaction is dissociated, and AMBRA1 associates with Beclin 1 at the endoplasmic reticulum (ER) and mitochondria to stimulate autophagy. Bcl-2 can thus regulate the initiation of autophagy at the ER as well as at mitochondrial membranes. In addition, binding between AMBRA1 and mito-BCL-2 is reduced during apoptosis and this may enhance the anti-apoptotic functions of Bcl-2. This work provides important novel insight into the importance of subcellular location on the activity of autophagy proteins and the crosstalk between autophagy and apoptosis. Autophagy is a conserved process of self-digestion, ‘self-eating’, which is utilized by cells in all multi-cellular organisms to survive a variety of stressful conditions, including nutrient deprivation, environmental changes, and infection. In addition, autophagy has a key role during development, in prevention of disease, and aging, although paradoxically autophagy may not always be beneficial. Given the complex and wide-ranging role of autophagy, it is perhaps not surprising that it is a highly regulated process. Currently, there are over 34 proteins that are required for autophagy. They were first systematically identified in yeast and called Atg (autophagy related) proteins (Yang and Klionsky, 2010). The function of these 34 Atg proteins is almost entirely dedicated to making autophagosomes with the correct composition and content. A subset of these Atg proteins function at the site of autophagosome formation that remains somewhat enigmatic: recently the ER, the Golgi, mitochondria, and plasma membrane have all been implicated in autophagosome formation. Under nutrient deprivation, aminoacid starvation in particular, the ER appears to be the site where most autophagosome formation occurs (Tooze and Yoshimori, 2010). One key Atg-containing complex is the autophagy-specific class III phosphatidylinositol 3-kinase (PI3P-kinase), which produces PI3P at the site of autophagosome formation (Simonsen and Tooze, 2009). In metazoans, this lipid kinase complex is composed of a kinase, hVps34, its regulatory partner p150, and Beclin 1 (Atg6 in yeast). Beclin 1 exists in several complexes involved in autophagosome formation and maturation. Two proteins that are essential for the function of the complex in autophagosome formation are Atg14L and AMBRA1. Atg14L is one of the first proteins that is translocated to the ER site of autophagosome formation (Matsunaga et al, 2010). In response to autophagic stimuli, AMBRA1 associates with Beclin 1 and becomes part of the