Involvement of valosin-containing protein (VCP)/p97 in the formation and clearance of abnormal protein aggregates

Taeko Kobayashi, Atsushi Manno, Akira Kakizuka
Genes to Cells: Devoted to Molecular & Cellular Mechanisms 2007, 12 (7): 889-901
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.

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