title: Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death.
abstract: Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase and its dysregulation is implicated in neurodegenerative diseases. Likewise, C-terminus of Hsc70-interacting protein (CHIP) is linked to neurological disorders, serving as an E3 ubiquitin ligase for targeting damaged or toxic proteins for proteasomal degradation. Here, we demonstrate that CHIP is a novel substrate for Cdk5. Cdk5 phosphorylates CHIP at Ser20 via direct binding to a highly charged domain of CHIP. Co-immunoprecipitation and ubiquitination assays reveal that Cdk5-mediated phosphorylation disrupts the interaction between CHIP and truncated apoptosis-inducing factor (tAIF) without affecting CHIP's E3 ligase activity, resulting in the inhibition of CHIP-mediated degradation of tAIF. Lentiviral transduction assay shows that knockdown of Cdk5 or overexpression of CHIP(S20A), but not CHIP(WT), attenuates tAIF-mediated neuronal cell death induced by hydrogen peroxide. Thus, we conclude that Cdk5-mediated phosphorylation of CHIP negatively regulates its neuroprotective function, thereby contributing to neuronal cell death progression following neurotoxic stimuli.
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.|Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: C
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.
authors.forename: N
authors.initials: N
authors.lastname: Yun
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Technion Rapport Faculty of Medicine, Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases Haifa, Haifa 30196, Israel.
authors.forename: M B H
authors.initials: MB
authors.lastname: Youdim
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 136-705, Korea.
authors.forename: C
authors.initials: C
authors.lastname: Ju
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 136-705, Korea.
authors.forename: W-K
authors.initials: WK
authors.lastname: Kim
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: P-L
authors.initials: PL
authors.lastname: Han
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Oh
mesh_terms: D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000502:physiology*; D051360:Cyclin-Dependent Kinase 5 / Q000737:chemistry / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D006861:Hydrogen Peroxide; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D046988:Proteasome Endopeptidase Complex