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.