Show simple item record Tresse, E Salomons, FA Vesa, J Bott, LC Kimonis, V Yao, TP Dantuma, NP Taylor, JP
dc.coverage.spatial United States 2011-06-21T17:22:00Z 2010-02
dc.identifier 11014
dc.identifier.citation Autophagy, 2010, 6 (2), pp. 217 - 227
dc.description.abstract VCP (VCP/p97) is a ubiquitously expressed member of the AAA(+)-ATPase family of chaperone-like proteins that regulates numerous cellular processes including chromatin decondensation, homotypic membrane fusion and ubiquitin-dependent protein degradation by the proteasome. Mutations in VCP cause a multisystem degenerative disease consisting of inclusion body myopathy, Paget disease of bone, and frontotemporal dementia (IBMPFD). Here we show that VCP is essential for autophagosome maturation. We generated cells stably expressing dual-tagged LC3 (mCherry-EGFP-LC3) which permit monitoring of autophagosome maturation. We determined that VCP deficiency by RNAi-mediated knockdown or overexpression of dominant-negative VCP results in significant accumulation of immature autophagic vesicles, some of which are abnormally large, acidified and exhibit cathepsin B activity. Furthermore, expression of disease-associated VCP mutants (R155H and A232E) also causes this autophagy defect. VCP was found to be essential to autophagosome maturation under basal conditions and in cells challenged by proteasome inhibition, but not in cells challenged by starvation, suggesting that VCP might be selectively required for autophagic degradation of ubiquitinated substrates. Indeed, a high percentage of the accumulated autophagic vesicles contain ubiquitin-positive contents, a feature that is not observed in autophagic vesicles that accumulate following starvation or treatment with Bafilomycin A. Finally, we show accumulation of numerous, large LAMP-1 and LAMP-2-positive vacuoles and accumulation of LC3-II in myoblasts derived from patients with IBMPFD. We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes and that defect in this function may contribute to IBMPFD pathogenesis.
dc.format.extent 217 - 227
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof Autophagy
dc.subject Adenosine Triphosphatases
dc.subject Animals
dc.subject Cathepsin B
dc.subject Cell Cycle Proteins
dc.subject Cells, Cultured
dc.subject Frontotemporal Dementia
dc.subject Humans
dc.subject Lysosomal-Associated Membrane Protein 1
dc.subject Lysosomal-Associated Membrane Protein 2
dc.subject Mice
dc.subject Microtubule-Associated Proteins
dc.subject Mutation
dc.subject Myoblasts
dc.subject Myositis, Inclusion Body
dc.subject Osteitis Deformans
dc.subject Phagosomes
dc.subject Proteasome Endopeptidase Complex
dc.subject RNA Interference
dc.subject Recombinant Fusion Proteins
dc.subject Syndrome
dc.subject Ubiquitin
dc.subject Vacuoles
dc.title VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US 2010-2-16 en_US
duke.description.endpage 227 en_US
duke.description.issue 2 en_US
duke.description.startpage 217 en_US
duke.description.volume 6 en_US
dc.relation.journal Autophagy en_US
pubs.issue 2
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Pharmacology & Cancer Biology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Radiation Oncology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published
pubs.volume 6
dc.identifier.eissn 1554-8635

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