title: Glycogen synthase kinase 3β 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 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.
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Eunju
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Hye Guk
authors.initials: HG
authors.lastname: Ryu
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.|Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States of America.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States of America.
authors.forename: Sangjune
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Dohyun
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Young-Hun
authors.initials: YH
authors.lastname: Jeong
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.|Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Kyong-Tai
authors.initials: KT
authors.lastname: Kim
mesh_terms: D056404:Chaperonin Containing TCP-1 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D000071058:Huntingtin Protein / Q000737:chemistry / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D066329:Protein Aggregates / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D010455:Peptides; D066329:Protein Aggregates; C097188:polyglutamine; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; C109891:VRK2 protein, human; D056404:Chaperonin Containing TCP-1