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

Abstract

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.