Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation.
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.
Pubmed ID: 19229105
- Xiong H
- Wang D
- Chen L
- Choo YS
- Ma H
- Tang C
- Xia K
- Jiang W
- Ronai Z
- Zhuang X
- Zhang Z
The Journal of clinical investigation
March 2, 2009
- Agency: NIEHS NIH HHS, Id: P01 ES 016738
- Agency: NIDCD NIH HHS, Id: R01 DC 006497
- Agency: NINDS NIH HHS, Id: R01 NS 057289
- Cell Line, Tumor
- Gene Deletion
- Genes, Recessive
- Intracellular Signaling Peptides and Proteins
- Oncogene Proteins
- Parkinson Disease
- Protein Denaturation
- RNA, Messenger
- Ubiquitin-Protein Ligases
- Parkinson disease, juvenile, type 2 is related to genes PRKN, PARK2, PDJ, LPRS2 which are autosomal recessive according to the OMIM database.
- Parkinson disease 6, early onset is related to genes PINK1, PARK6 which are autosomal recessive according to the OMIM database.
- Leprosy, susceptibility to is related to genes PRKN, PARK2, PDJ, LPRS2.
- Parkinson disease 7, autosomal recessive early-onset is related to genes DJ1, PARK7 which are autosomal recessive according to the OMIM database.
- Adenocarcinoma, ovarian, somatic is related to genes PRKN, PARK2, PDJ, LPRS2 which are autosomal dominant according to the OMIM database.
- Adenocarcinoma of lung, somatic is related to genes PRKN, PARK2, PDJ, LPRS2 which are autosomal recessive according to the OMIM database.