title: Vaccinia-related kinase 2 mediates accumulation of polyglutamine aggregates via negative regulation of the chaperonin TRiC.
abstract: Misfolding of proteins containing abnormal expansions of polyglutamine (polyQ) repeats is associated with cytotoxicity in several neurodegenerative disorders, including Huntington's disease. Recently, the eukaryotic chaperonin TRiC hetero-oligomeric complex has been shown to play an important role in protecting cells against the accumulation of misfolded polyQ protein aggregates. It is essential to elucidate how TRiC function is regulated to better understand the pathological mechanism of polyQ aggregation. Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not. Interestingly, VRK2-mediated downregulation of TRiC increased aggregate formation of a polyQ-expanded huntingtin fragment. This effect was ameliorated by rescue of TRiC protein levels. Notably, small interference RNA-mediated knockdown of VRK2 enhanced TRiC protein stability and decreased polyQ aggregation. The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.
authors.affiliation: Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Sangjune
authors.initials: S
authors.lastname: Kim
authors.forename: Do-Young
authors.initials: DY
authors.lastname: Park
authors.forename: Dohyun
authors.initials: D
authors.lastname: Lee
authors.forename: Wanil
authors.initials: W
authors.lastname: Kim
authors.forename: Young-Hun
authors.initials: YH
authors.lastname: Jeong
authors.forename: Juhyun
authors.initials: J
authors.lastname: Lee
authors.forename: Sung-Kee
authors.initials: SK
authors.lastname: Chung
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Ha
authors.forename: Bo-Hwa
authors.initials: BH
authors.lastname: Choi
authors.forename: Kyong-Tai
authors.initials: KT
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056404:Chaperonin Containing TCP-1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C533300:CCT4 protein, human; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine; D017346:Protein Serine-Threonine Kinases; C109891:VRK2 protein, human; D056404:Chaperonin Containing TCP-1