Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease.
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.
Ju
Jeong-Sun
JS
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Fuentealba
Rodrigo A
RA
Miller
Sara E
SE
Jackson
Erin
E
Piwnica-Worms
David
D
Baloh
Robert H
RH
Weihl
Conrad C
CC
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D001706:Biopsy; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002738:Chloroquine; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D057180:Frontotemporal Dementia / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010001:Osteitis Deformans / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D052097:Quadriceps Muscle / Q000201:enzymology* / Q000473:pathology; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D000074405:Valosin Containing Protein
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; C477012:MAP1LC3A protein, human; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin; D002738:Chloroquine; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse