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, Young Jun Oh

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 languageEnglish
Pages (from-to)333-346
Number of pages14
JournalCell Death and Differentiation
Volume23
Issue number2
DOIs
Publication statusPublished - 2016 Feb 1

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HSC70 Heat-Shock Proteins
Cyclin-Dependent Kinase 5
Apoptosis Inducing Factor
Phosphorylation
Ubiquitin-Protein Ligases
Proteolysis
Cell Death
Poisons
Protein-Serine-Threonine Kinases
Ubiquitination
Nervous System Diseases
Immunoprecipitation
Proline
Neurodegenerative Diseases
Hydrogen Peroxide

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Kim, C. ; Yun, N. ; Lee, J. ; Youdim, M. B.H. ; Ju, C. ; Kim, W. K. ; Han, P. L. ; Oh, Young Jun. / Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death. In: Cell Death and Differentiation. 2016 ; Vol. 23, No. 2. pp. 333-346.
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Kim, C, Yun, N, Lee, J, Youdim, MBH, Ju, C, Kim, WK, Han, PL & Oh, YJ 2016, 'Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death', Cell Death and Differentiation, vol. 23, no. 2, pp. 333-346. https://doi.org/10.1038/cdd.2015.103

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death. / Kim, C.; Yun, N.; Lee, J.; Youdim, M. B.H.; Ju, C.; Kim, W. K.; Han, P. L.; Oh, Young Jun.

In: Cell Death and Differentiation, Vol. 23, No. 2, 01.02.2016, p. 333-346.

Research output: Contribution to journalArticle

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AU - Yun, N.

AU - Lee, J.

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AU - Kim, W. K.

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AU - Oh, Young Jun

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