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Glycogen synthase kinase 3? suppresses polyglutamine aggregation by inhibiting Vaccinia-related kinase 2 activity.

ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the N-terminal of huntingtin. The amount of aggregate-prone protein is controlled by various mechanisms, including molecular chaperones. Vaccinia-related kinase 2 (VRK2) is known to negatively regulate chaperonin TRiC, and VRK2-facilitated degradation of TRiC increases polyQ protein aggregation, which is involved in HD. We found that VRK2 activity was negatively controlled by glycogen synthase kinase 3? (GSK3?). GSK3? directly bound to VRK2 and inhibited the catalytic activity of VRK2 in a kinase activity-independent manner. Furthermore, GSK3? increased the stability of TRiC and decreased the formation of HttQ103-GFP aggregates by inhibiting VRK2. These results indicate that GSK3? signaling may be a regulatory mechanism of HD progression and suggest targets for further therapeutic trials for HD.

SUBMITTER: Lee E 

PROVIDER: S-EPMC4932512 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Glycogen synthase kinase 3β suppresses polyglutamine aggregation by inhibiting Vaccinia-related kinase 2 activity.

Lee Eunju E   Ryu Hye Guk HG   Kim Sangjune S   Lee Dohyun D   Jeong Young-Hun YH   Kim Kyong-Tai KT  

Scientific reports 20160705

Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the N-terminal of huntingtin. The amount of aggregate-prone protein is controlled by various mechanisms, including molecular chaperones. Vaccinia-related kinase 2 (VRK2) is known to negatively regulate chaperonin TRiC, and VRK2-facilitated degradation of TRiC increases polyQ protein aggregation, which is involved in HD. We found that VRK2 activity was negatively controlled by gly  ...[more]

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