E3 ubiquitin-protein ligase TRIM63
ubiquitin protein ligase activity
Loss of UCHL1 rescues the defects related to Parkinson's disease by suppressing glycolysis.
The role of ubiquitin carboxyl-terminal hydrolase L1 (<i>UCHL1</i>; also called <i>PARK5</i>) in the pathogenesis of Parkinson's disease (PD) has been controversial. Here, we find that the loss of UCHL1 destabilizes pyruvate kinase (PKM) and mitigates the PD-related phenotypes induced by PTEN-induced kinase 1 (<i>PINK1</i>) or <i>Parkin</i> loss-of-function mutations in <i>Drosophila</i> and mammalian cells. In UCHL1 knockout cells, cellular pyruvate production and ATP levels are diminished, and the activity of AMP-activated protein kinase (AMPK) is highly induced. Consequently, the activated AMPK promotes the mitophagy mediated by Unc-51-like kinase 1 (ULK1) and FUN14 domain-containing 1 (FUNDC1), which underlies the effects of UCHL1 deficiency in rescuing PD-related defects. Furthermore, we identify tripartite motif-containing 63 (TRIM63) as a previously unknown E3 ligase of PKM and demonstrate its antagonistic interaction with UCHL1 to regulate PD-related pathologies. These results suggest that UCHL1 is an integrative factor for connecting glycolysis and PD pathology.