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

Eunju Lee,Young-Hun Jeong,Kyong-Tai Kim,Hye Guk Ryu,Sangjune Kim,Dohyun Lee

doi:10.1038/srep29097

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 3β (GSK3β). GSK3β directly bound to VRK2 and inhibited the catalytic activity of VRK2 in a kinase activity-independent manner. Furthermore, GSK3β increased the stability of TRiC and decreased the formation of HttQ103-GFP aggregates by inhibiting VRK2. These results indicate that GSK3β signaling may be a regulatory mechanism of HD progression and suggest targets for further therapeutic trials for HD.

Highlights

Glycogen synthase kinase 3 (GSK3) is a constitutively active serine/threonine kinase with two isoforms: GSK3αand GSK3β15
We previously found that VRK2 indirectly affects the folding of polyQ proteins involved in HD9,14
To examine whether other proteins are involved in the regulation of VRK2mediated polyQ protein aggregation, we carried out immunoprecipitation analysis

Summary

Introduction

Glycogen synthase kinase 3 (GSK3) is a constitutively active serine/threonine kinase with two isoforms: GSK3αand GSK3β15. Its kinase activity is regulated by inhibitory phosphorylation sites at serine-21 and serine-9 in GSK3αand GSK3β, respectively[16]. GSK3βhas several substrates and is involved in many cellular processes, including cell development[19], proliferation, cell migration[20], glucose regulation, and apoptosis[18]. Consistent with its involvement in a variety of signaling pathways, GSK3βis associated with many diseases such as Alzheimer’s disease[21], cancer[22,23], bipolar disorder[24], diabetes[22], and HD. Decreased GSK3βlevels and activity are observed in the brains of R6/1 mice, an animal model of HD25, and reduced GSK3βlevels are found in the brains of human patients with HD26. We show that GSK3βdirectly interacted with VRK2 and inhibited VRK2 catalytic activity in vitro. GSK3βreduced VRK2-mediated degradation of TRiC, thereby suppressing polyQ-expanded Htt aggregation

Methods

Results

Conclusion