Human Molecular Genetics Advance Access originally published online on December 1, 2005
Human Molecular Genetics 2006 15(2):189-199; doi:10.1093/hmg/ddi426
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Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation
1Department of Neurology 2Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
* To whom correspondence should be addressed at: Department of Neurology, Washington University School of Medicine, PO Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, USA. Tel: +1 3143626981; Fax: +1 3143623752; Email: weihlc{at}neuro.wustl.edu
Received September 24, 2005; Accepted November 12, 2005
Mutations in the AAA+ protein (ATPase associated with a variety of cellular activities) p97/VCP (valosin-containing protein) cause a dominantly inherited syndrome of inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia (IBMPFD). p97/VCP is a ubiquitously expressed protein that participates in a number of cellular processes including endoplasmic reticulum-associated degradation (ERAD). p97/VCP aids in the extraction of ubiquitinated proteins from the endoplasmic reticulum (ER) and facilitates their delivery to the proteasome. This study focusses on the effects of disease-associated p97/VCP mutations on this pathway. We show that p97/VCP containing the most prevalent IBMPFD-associated mutation, R155H, has normal ATPase activity and hexameric structure. However, when expressed in cultured cells, both this and a second IBMPFD-associated p97/VCP mutant increase the overall level of ubiquitin-conjugated proteins and specifically impair degradation of mutant 
F508-CFTR handled by the ERAD pathway. These effects are similar to those previously described for an ATPase deficient p97/VCP mutant and suggest that IBMPFD mutations impair p97/VCP cellular function. In a subset of cells, IBMPFD mutations also promote formation of aggregates that contain p97/VCP, ubiquitin conjugates and ER-resident proteins. Undegraded mutant F508-CFTR also accumulates in these aggregates. We conclude that IBMPFD mutations in p97/VCP disrupt ERAD and that this may contribute to the pathogenesis of IBMPFD.
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