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

Title
Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death
Authors
Kim, C.Yun, N.Lee, J.Youdim, M. B. H.Ju, C.Kim, W-KHan, P-LOh, Y. J.
Ewha Authors
한평림
SCOPUS Author ID
한평림scopus
Issue Date
2016
Journal Title
CELL DEATH AND DIFFERENTIATION
ISSN
1350-9047JCR Link1476-5403JCR Link
Citation
vol. 23, no. 2, pp. 333 - 346
Publisher
NATURE PUBLISHING GROUP
Indexed
SCI; SCIE; SCOPUS WOS 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 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.
DOI
10.1038/cdd.2015.103
Appears in Collections:
일반대학원 > 뇌·인지과학과 > Journal papers
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