%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