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.
Xiong
Hui
H
Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Wang
Danling
D
Chen
Linan
L
Choo
Yeun Su
YS
Ma
Hong
H
Tang
Chengyuan
C
Xia
Kun
K
Jiang
Wei
W
Ronai
Ze'ev
Z
Zhuang
Xiaoxi
X
Zhang
Zhuohua
Z
D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D017353:Gene Deletion; D005808:Genes, Recessive; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics*; D000071617:Protein Deglycase DJ-1; D011489:Protein Denaturation; D012333:RNA, Messenger / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; C497604:SNCA protein, human; D025801:Ubiquitin; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1