Antagonism of Beclin 1-dependent autophagy by BCL-2 at the endoplasmic reticulum requires NAF-1

In addition to mitochondria, Bcl-2 is located at the endoplasmic reticulum (ER) where it is a constituent of several distinct complexes. Here, we identify the BCL-2-interacting protein at the ER, nutrient-deprivation Autophagy factor-1 (NAF-1)-a bitopic integral membrane protein whose defective expression underlies the aetiology of the neurodegenerative disorder Wolfram syndrome 2 (WFS2). NAF-1 contains a two iron-two sulphur coordinating domain within its cytosolic region, which is necessary, but not sufficient for interaction with Bcl-2. NAF-1 is displaced from Bcl-2 by the ER-restricted BH3-only protein BIK and contributes to regulation of BIK-initiated Autophagy, but not BIK-dependent activation of caspases. Similar to Bcl-2, NAF-1 is found in association with the inositol 1,4,5-triphosphate receptor and is required for BCL-2-mediated depression of ER Ca(2+) stores. During nutrient deprivation as a physiological stimulus of Autophagy, Bcl-2 is known to function through inhibition of the Autophagy effector and tumour suppressor Beclin 1. NAF-1 is required in this pathway for Bcl-2 at the ER to functionally antagonize Beclin 1-dependent Autophagy. Thus, NAF-1 is a BCL-2-associated co-factor that targets Bcl-2 for antagonism of the Autophagy pathway at the ER.