Derlin-1 Regulates Mutant VCP-Linked Pathogenesis and Endoplasmic Reticulum Stress-Induced Apoptosis

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. © 2014 liang et al.