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- Title
Derlin-1 Regulates Mutant VCP-Linked Pathogenesis and Endoplasmic Reticulum Stress-Induced Apoptosis.
- Authors
Liang, Cyong-Jhih; Chang, Ya-Chu; Chang, Henry C.; Wang, Chung-Kang; Hung, Yu-Chien; Lin, Ying-Er; Chan, Chia-Ching; Chen, Chun-Hong; Chang, Hui-Yun; Sang, Tzu-Kang
- 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.
- Subjects
DROSOPHILA genetics; ENDOPLASMIC reticulum; ANIMAL mutation; APOPTOSIS; PHYSIOLOGICAL stress; INSECTS
- Publication
PLoS Genetics, 2014, Vol 10, Issue 9, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1004675