Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Apoptosis Regulatory Proteins / antagonists & inhibitors*
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis Regulatory Proteins / physiology
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Autophagy* / drug effects
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Autophagy* / genetics
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Autophagy* / physiology
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Beclin-1
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Caspases / metabolism
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism*
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Endoplasmic Reticulum / physiology
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Enzyme Activation / drug effects
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Humans
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / metabolism
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Membrane Proteins / physiology
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Mitochondrial Proteins
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Models, Biological
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Molecular Sequence Data
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Protein Binding / drug effects
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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RNA, Small Interfering / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / genetics
Substances
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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BIK protein, human
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Beclin-1
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DNA-Binding Proteins
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Membrane Proteins
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Mitochondrial Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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TNIP1 protein, human
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Caspases