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Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death
- 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, Y. J.
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- CELL DEATH AND DIFFERENTIATION
- CELL DEATH AND DIFFERENTIATION vol. 23, no. 2, pp. 333 - 346
- NATURE PUBLISHING GROUP
- SCIE; SCOPUS
- Document Type
- 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 CHIPS20A, but not CHIPWT, 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.
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