Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling.
Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.
Sha
Di
D
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Chin
Lih-Shen
LS
Li
Lian
L
D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D016328:NF-kappa B; D011494:Protein Kinases; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein