Human Molecular Genetics Advance Access first published online on October 30, 2009
This version [Corrected Proof] published online on November 11, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp501
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Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-
B signaling
Department of Pharmacology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA
* To whom correspondence should be addressed. Tel: +1 4047270361; Fax: +1 4047270365; Email: chinl{at}pharm.emory.edu/lianli{at}pharm.emory.edu
Received August 16, 2009; Accepted October 28, 2009
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 I
B kinase/nuclear factor B (NF-B) 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-B neuroprotective signaling pathway in the pathogenesis of PD.