title: Derlin-1 regulates mutant VCP-linked pathogenesis and endoplasmic reticulum stress-induced apoptosis.
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.
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Cyong-Jhih
authors.initials: CJ
authors.lastname: Liang
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ya-Chu
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chung-Kang
authors.initials: CK
authors.lastname: Wang
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yu-Chien
authors.initials: YC
authors.lastname: Hung
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ying-Er
authors.initials: YE
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chia-Ching
authors.initials: CC
authors.lastname: Chan
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan; Institute of Systems Neuroscience, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan; Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Tzu-Kang
authors.initials: TK
authors.lastname: Sang
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics; D004789:Enzyme Activation; D015870:Gene Expression; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008958:Models, Molecular; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D000074405:Valosin Containing Protein
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D020169:Caspases; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein; C585179:ter94 protein, Drosophila