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.
Chang
Natasha C
NC
Department of Biochemistry and Goodman Cancer Center, McGill University, Montreal, Quebec, Canada.
Nguyen
Mai
M
Germain
Marc
M
Shore
Gordon C
GC
D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000071186:Beclin-1; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D024101:Mitochondrial Proteins; D008954:Models, Biological; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; C096820:BIK protein, human; D000071186:Beclin-1; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C117046:TNIP1 protein, human; D020169:Caspases