Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

C. Kim, N. Yun, J. Lee, M. B.H. Youdim, C. Ju, W. K. Kim, P. L. Han, Y. J. Oh

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26 Citations (Scopus)


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 languageEnglish
Pages (from-to)333-346
Number of pages14
JournalCell Death and Differentiation
Issue number2
Publication statusPublished - 2016 Feb 1

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© 2016 Macmillan Publishers Limited All rights reserved.

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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