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.
Original language | English |
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Pages (from-to) | 333-346 |
Number of pages | 14 |
Journal | Cell Death and Differentiation |
Volume | 23 |
Issue number | 2 |
DOIs | |
State | Published - 1 Feb 2016 |
Bibliographical note
Funding Information:Acknowledgements. This work was supported by the National Research Foundation of Korea (NRF) grant through SRC (2008-0061888; YJO), by the Ministry for Health, Welfare and Family Affair (A111382; YJO, and by a grant from the Ministry of Science, ICT and Future Planning (2012R1A2A1A03010177; to P-LH).
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