Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation

Conrad C. Weihl, Seema Dalal, Alan Pestronk, Phyllis I. Hanson

Research output: Contribution to journalArticlepeer-review

149 Scopus citations


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 mostprevalent 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 ΔF508-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 ΔF508-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.

Original languageEnglish
Pages (from-to)189-199
Number of pages11
JournalHuman molecular genetics
Issue number2
StatePublished - Jan 15 2006


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