Abstract
Mutations in VCP (Valosin-containing protein), an AAA ATPase critical for ER-associated degradation, are linked to IBMPFD (Inclusion body myopathy with Paget disease and frontotemporal dementia). Using a Drosophila IBMPFD model, we have identified the ER protein Derlin-1 as a modifier of pathogenic TER94 (the fly VCP homolog) mutants. Derlin-1 binds to TER94 directly, and this interaction is essential for Derlin-1 overexpression to suppress the pathogenic TER94-induced neurodegeneration. Derlin-1 overexpression reduces the elevated ATPase activity of pathogenic TER94, implying that IBMPFD is caused by ATPase hyper-activation. Under physiological condition, Derlin-1 expression is increased upon ER stress to recruit TER94 to the ER. However, in response to severe ER stress, Derlin-1 is required for activating apoptosis to eliminate damaged cells. This pro-apoptotic response is mimicked by Derlin-1 overexpression, which elicits acute ER stress and triggers apoptosis via a novel C-terminal motif (α). As this Derlin-1-dependent cell death is negated by TER94 overexpression, we propose that while Derlin-1 and VCP work cooperatively in ER stress response, their imbalance has a role in removing cells suffering prolonged ER stress.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases / genetics*
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Animals
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Apoptosis / genetics*
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Caspases / metabolism
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Disease Models, Animal
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Drosophila
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Drosophila Proteins / genetics*
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Drosophila Proteins / metabolism
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Endoplasmic Reticulum Stress / genetics*
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Endoplasmic Reticulum-Associated Degradation / genetics
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Enzyme Activation
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Gene Expression
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Membrane Proteins / chemistry
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mitochondria / genetics
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Mitochondria / metabolism
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Mitochondria / pathology
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Mitochondria / ultrastructure
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Models, Molecular
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Mutation*
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Neurodegenerative Diseases / genetics
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Neurodegenerative Diseases / metabolism
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Phenotype
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Protein Binding
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Protein Conformation
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Protein Interaction Domains and Motifs
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Valosin Containing Protein
Substances
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Drosophila Proteins
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Membrane Proteins
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Caspases
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Adenosine Triphosphatases
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Valosin Containing Protein
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ter94 protein, Drosophila
Grants and funding
This work was supported by a grant from the Ministry of Science and Technology (
http://web1.most.gov.tw) to TKS (102-2311-B-007-001 and 103-2311-B-007-006-MY3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.