Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease

Jeong Sun Ju, Rodrigo A. Fuentealba, Sara E. Miller, Erin Jackson, David Piwnica-Worms, Robert H. Baloh, Conrad C. Weihl

Research output: Contribution to journalArticle

317 Scopus citations

Abstract

Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM), Paget's disease of the bone, and frontotemporal dementia (IBMPFD). Patient muscle has degenerating fibers, rimmed vacuoles (RVs), and sarcoplasmic inclusions containing ubiquitin and TDP-43 (TARDNA-binding protein 43). In this study, we find that IBMPFD muscle also accumulates autophagosome-associated proteins, Map1-LC3 (LC3), and p62/sequestosome, which localize to RVs. To test whether VCP participates in autophagy, we silenced VCP or expressed adenosine triphosphatase-inactive VCP. Under basal conditions, loss of VCP activity results in autophagosome accumulation. After autophagic induction, these autophagosomes fail to mature into autolysosomes and degrade LC3. Similarly, IBMPFD mutant VCP expression in cells and animals leads to the accumulation of nondegradative autophagosomes that coalesce at RVs and fail to degrade aggregated proteins. Interestingly, TDP-43 accumulates in the cytosol upon autophagic inhibition, similar to that seen after IBMPFD mutant expression. These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.

Original languageEnglish
Pages (from-to)875-888
Number of pages14
JournalJournal of Cell Biology
Volume187
Issue number6
DOIs
StatePublished - Dec 14 2009

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    Ju, J. S., Fuentealba, R. A., Miller, S. E., Jackson, E., Piwnica-Worms, D., Baloh, R. H., & Weihl, C. C. (2009). Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. Journal of Cell Biology, 187(6), 875-888. https://doi.org/10.1083/jcb.200908115