期刊
CELL DEATH AND DIFFERENTIATION
卷 23, 期 2, 页码 333-346出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2015.103
关键词
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资金
- National Research Foundation of Korea (NRF) through SRC [2008-0061888]
- Ministry for Health, Welfare and Family Affair [A111382]
- Ministry of Science, ICT and Future Planning [2012R1A2A1A03010177]
- National Research Foundation of Korea [2008-0061888] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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