Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation

• Published in: The Journal of clinical investigation 2009-03, Vol.119 (3), p.650-660
• Main Authors: Xiong, Hui, Wang, Danling, Chen, Linan, Choo, Yeun Su, Ma, Hong, Tang, Chengyuan, Xia, Kun, Jiang, Wei, Ronai, Ze'ev, Zhuang, Xiaoxi, Zhang, Zhuohua
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - deficiency; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Biomedical research; Brain; Cell Line, Tumor; Cytosol - metabolism; Development and progression; Diagnosis; Gene Deletion; Genes, Recessive; Glycoproteins; Humans; Insects; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Localization; Mitochondria - genetics; Mitochondria - metabolism; Mutation; Neuroblastoma; Oncogene Proteins - deficiency; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oxidative stress; Parkinson Disease - genetics; Parkinson's disease; Pathogenesis; Physiological aspects; Prevention; Protein Deglycase DJ-1; Protein Denaturation; Proteins; Proteolysis; RNA, Messenger - genetics; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI37617

Mutations in PARKIN, pten-induced putative kinase 1 (PINK1), and DJ-1 are individually linked to autosomal recessive early-onset familial forms of Parkinson disease (PD). Although mutations in these genes lead to the same disease state, the functional relationships between them and how their respective disease-associated mutations cause PD are largely unknown. Here, we show that Parkin, PINK1, and DJ-1 formed a complex (termed PPD complex) to promote ubiquitination and degradation of Parkin substrates, including Parkin itself and Synphilin-1 in neuroblastoma cells and human brain lysates. Genetic ablation of either Pink1 or Dj-1 resulted in reduced ubiquitination of endogenous Parkin as well as decreased degradation and increased accumulation of aberrantly expressed Parkin substrates. Expression of PINK1 enhanced Parkin-mediated degradation of heat shock-induced misfolded protein. In contrast, PD-pathogenic Parkin and PINK1 mutations showed reduced ability to promote degradation of Parkin substrates. This study identified a functional ubiquitin E3 ligase complex consisting of PD-associated Parkin, PINK1, and DJ-1 to promote degradation of un-/misfolded proteins and suggests that their PD-pathogenic mutations impair E3 ligase activity of the complex, which may constitute a mechanism underlying PD pathogenesis.