TY - JOUR
T1 - Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death
AU - Kim, C.
AU - Yun, N.
AU - Lee, J.
AU - Youdim, M. B.H.
AU - Ju, C.
AU - Kim, W. K.
AU - Han, P. L.
AU - Oh, Y. J.
N1 - Funding Information:
Acknowledgements. This work was supported by the National Research Foundation of Korea (NRF) grant through SRC (2008-0061888; YJO), by the Ministry for Health, Welfare and Family Affair (A111382; YJO, and by a grant from the Ministry of Science, ICT and Future Planning (2012R1A2A1A03010177; to P-LH).
Publisher Copyright:
© 2016 Macmillan Publishers Limited All rights reserved.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84954078841&partnerID=8YFLogxK
U2 - 10.1038/cdd.2015.103
DO - 10.1038/cdd.2015.103
M3 - Article
C2 - 26206088
AN - SCOPUS:84954078841
SN - 1350-9047
VL - 23
SP - 333
EP - 346
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 2
ER -