Vaccinia-related kinase 2 mediates accumulation of polyglutamine aggregates via negative regulation of the chaperonin TRiC.

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.
AuthorsSangjune Kim, Do-Young Park, Dohyun Lee, Wanil Kim, Young-Hun Jeong, Juhyun Lee, Sung-Kee Chung, Hyunjung Ha, Bo-Hwa Choi, Kyong-Tai Kim
JournalMolecular and cellular biology (Mol Cell Biol) Vol. 34 Issue 4 Pg. 643-52 (Feb 2014) ISSN: 1098-5549 [Electronic] United States
PMID24298020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CCT4 protein, human
  • HTT protein, human
  • Nerve Tissue Proteins
  • Peptides
  • polyglutamine
  • Protein-Serine-Threonine Kinases
  • VRK2 protein, human
  • Chaperonin Containing TCP-1
  • Animals
  • Cells, Cultured
  • Chaperonin Containing TCP-1 (metabolism)
  • Gene Expression Regulation (physiology)
  • Humans
  • Huntington Disease (metabolism)
  • Mice
  • Mutation (genetics)
  • Nerve Tissue Proteins (genetics, metabolism)
  • Peptides (metabolism)
  • Protein Folding
  • Protein-Serine-Threonine Kinases (metabolism)

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