Involvement of valosin-containing protein (VCP)/p97 in the formation and clearance of abnormal protein aggregates.
Abnormal protein aggregates are commonly observed in affected neurons in many neurodegenerative disorders. We have reported that valosin-containing protein (VCP) co-localizes with protein aggregates in patients' neurons and in cultured cells expressing diseased proteins. However, the significance of such co-localization remains elucidated. Here we report the involvement of VCP in the re-solubilization process of abnormal protein aggregates. VCP recognized and accumulated onto pre-formed protein aggregates created by proteasome inhibition. VCP knockdown or the expression of dominant-negative VCP both significantly delayed the elimination of ubiquitin-positive aggregates. VCP was involved in the clearance of pre-formed polyglutamine aggregates as well. Paradoxically, VCP knockdown also diminished polyglutamine aggregate formation. Furthermore, its ATPase activity was required for the re-solubilization and re-activation of heat-denatured proteins, such as luciferase, from insoluble aggregates. We thus propose that VCP functions as a mediator for both aggregate formation and clearance depending upon the concentration of soluble aggregate-prone proteins, indicating dual VCP functions as an aggregate formase and an unfoldase.
Kobayashi
Taeko
T
Laboratory of Functional Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
Manno
Atsushi
A
Kakizuka
Akira
A
D000251:Adenosine Triphosphatases / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008156:Luciferases / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism / Q000502:physiology; D016716:PC12 Cells; D010455:Peptides / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011489:Protein Denaturation; D051381:Rats; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D018832:Molecular Chaperones; D010455:Peptides; C097188:polyglutamine; D008156:Luciferases; D043743:Ubiquitin-Protein Ligase Complexes; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614180:Vcp protein, rat