%0 Journal Article
%T Derlin-1 Regulates Mutant VCP-Linked Pathogenesis and Endoplasmic Reticulum Stress-Induced Apoptosis
%A Chia-Ching Chan
%A Chun-Hong Chen
%A Chung-Kang Wang
%A Cyong-Jhih Liang
%A Henry C. Chang
%A Hui-Yun Chang
%A Tzu-Kang Sang
%A Ya-Chu Chang
%A Ying-Er Lin
%A Yu-Chien Hung
%J -
%D 2014
%R 10.1371/journal.pgen.1004675
%X 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 (¦Á). 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
%K Eyes
%K Adenosine triphosphatase
%K Photoreceptors
%K Apoptosis
%K Hyperexpression techniques
%K Mitochondria
%K Endoplasmic reticulum
%K Immunoprecipitation
%U https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004675