ABSTRACT
Mutations in the Park2 gene, encoding the E3 ubiquitin-ligase parkin, are responsible for a familial form of Parkinson's disease (PD). Parkin-mediated ubiquitination is critical for the efficient elimination of depolarized dysfunctional mitochondria by autophagy (mitophagy). As damaged mitochondria are a major source of toxic reactive oxygen species within the cell, this pathway is believed to be highly relevant to the pathogenesis of PD. Little is known about how parkin-mediated ubiquitination is regulated during mitophagy or about the nature of the ubiquitin conjugates involved. We report here that USP8/UBPY, a deubiquitinating enzyme not previously implicated in mitochondrial quality control, is critical for parkin-mediated mitophagy. USP8 preferentially removes non-canonical K6-linked ubiquitin chains from parkin, a process required for the efficient recruitment of parkin to depolarized mitochondria and for their subsequent elimination by mitophagy. This work uncovers a novel role for USP8-mediated deubiquitination of K6-linked ubiquitin conjugates from parkin in mitochondrial quality control.
Subject(s)
Endopeptidases/metabolism , Endosomal Sorting Complexes Required for Transport/metabolism , Mitochondria/metabolism , Mitophagy/physiology , Ubiquitin Thiolesterase/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination/physiology , Endopeptidases/genetics , Endosomal Sorting Complexes Required for Transport/genetics , HEK293 Cells , HeLa Cells , Humans , Mitochondria/genetics , Ubiquitin Thiolesterase/genetics , Ubiquitin-Protein Ligases/geneticsABSTRACT
OBJECTIVE: Several genome-wide association studies and replication analyses have identified common variation at the insulin-like binding protein 2 (IGF2BP2) gene to be associated with type 2 diabetes (T2DM). The aim of this study was to replicate in a Lebanese Arab population identified associations of IGF2BP2 variants rs4402960 and rs1470579 with T2DM. METHODS: This case-control study involved 544 T2DM patients and 606 control subjects. Genotyping was done by the allelic exclusion method. RESULTS: T allele of rs440960 (P=6.5 × 10(-6)) and C allele of rs1470579 (P=5.3 × 10(-4)) were significantly associated with T2DM; both SNPs were in strong LD (D'=0.83, r(2)=0.58). While both IGF2BP2 SNPs were significantly associated with T2DM under additive and recessive models, only rs4402960 remained significantly associated with T2DM under the dominant model. Taking the common rs4402960/rs1470579 GA haplotype as reference, multivariate analysis confirmed the positive association of TC (P=0.009; OR, 1.43; 95%CI, 1.09-1.87), and TA (P<0.001; OR=5.49; 95%CI=2.09-14.39) haplotypes with increased T2DM risk. These differences remained significant after applying the Bonferroni correction for multiple testing. CONCLUSION: We validate that IGF2BP2 susceptibility variants rs4402960 and rs1470579 associate with T2DM in Lebanese Arabs.
