The acetylation of cyclin-dependent kinase 5 at lysine 33 regulates kinase activity and neurite length in hippocampal neurons

Juhyung Lee; Yeon Uk Ko; Yuhyun Chung; Nuri Yun; Myungjin Kim; Kyungjin Kim; Young J. Oh

doi:10.1038/s41598-018-31785-9

The acetylation of cyclin-dependent kinase 5 at lysine 33 regulates kinase activity and neurite length in hippocampal neurons

Juhyung Lee, Yeon Uk Ko, Yuhyun Chung, Nuri Yun, Myungjin Kim, Kyungjin Kim, Young J. Oh

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Abstract

Cyclin-dependent kinase 5 (CDK5) plays a pivotal role in neural development and neurodegeneration. CDK5 activity can be regulated by posttranslational modifications, including phosphorylation and S-nitrosylation. In this study, we demonstrate a novel mechanism by which the acetylation of CDK5 at K33 (Ac-CDK5) results in the loss of ATP binding and impaired kinase activity. We identify GCN5 and SIRT1 as critical factor controlling Ac-CDK5 levels. Ac-CDK5 achieved its lowest levels in rat fetal brains but was dramatically increased during postnatal periods. Intriguingly, nuclear Ac-CDK5 levels negatively correlated with neurite length in embryonic hippocampal neurons. Either treatment with the SIRT1 activator SRT1720 or overexpression of SIRT1 leads to increases in neurite length, whereas SIRT1 inhibitor EX527 or ectopic expression of acetyl-mimetic (K33Q) CDK5 induced the opposite effect. Furthermore, the expression of nuclear-targeted CDK5 K33Q abolished the SRT1720-induced neurite outgrowth, showing that SIRT1 positively regulates neurite outgrowth via deacetylation of nuclear CDK5. The CDK5 activity-dependent increase of neurite length was mediated by enhanced transcriptional regulation of BDNF via unknown mechanism(s). Our findings identify a novel mechanism by which acetylation-mediated regulation of nuclear CDK5 activity plays a critical role in determining neurite length in embryonic neurons.

Original language	English
Article number	13676
Journal	Scientific reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-31785-9
Publication status	Published - 2018 Dec 1

Bibliographical note

Funding Information:
This work was supported by the Mid-Career Research Program (NRF; 2017R1A2B4007301 to YJO), and by the Brain Research Program through the National Research Foundation of Korea (2017M3C7A1025369 to YJO). This research was supported in part by the NRF-2014R1A2A1A01003680 (to KK), and by the Basic Research Program through Korea Brain Research Institute (KBRI) funded by Ministry of Science and ICT (18-BR-02-01 to MK). YUK and YHC are recipients of the BK21 Plus. We are grateful to Dr. Ja-Eun Kim (Kyunghee University), Dr. Jason W. Chin (University of Cambridge), Dr. Hyunsook Lee (Seoul National University) and Dr. Jacques Côte (Laval University) for providing plasmids, to Dr. Eutteum Jeong (Ewha Womans University) for helping real-time PCR analysis, and to Dr. Dongeun Park (Seoul National University) for his advice on neurite outgrowth analysis.

Publisher Copyright:
© 2018, The Author(s).

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title = "The acetylation of cyclin-dependent kinase 5 at lysine 33 regulates kinase activity and neurite length in hippocampal neurons",

abstract = "Cyclin-dependent kinase 5 (CDK5) plays a pivotal role in neural development and neurodegeneration. CDK5 activity can be regulated by posttranslational modifications, including phosphorylation and S-nitrosylation. In this study, we demonstrate a novel mechanism by which the acetylation of CDK5 at K33 (Ac-CDK5) results in the loss of ATP binding and impaired kinase activity. We identify GCN5 and SIRT1 as critical factor controlling Ac-CDK5 levels. Ac-CDK5 achieved its lowest levels in rat fetal brains but was dramatically increased during postnatal periods. Intriguingly, nuclear Ac-CDK5 levels negatively correlated with neurite length in embryonic hippocampal neurons. Either treatment with the SIRT1 activator SRT1720 or overexpression of SIRT1 leads to increases in neurite length, whereas SIRT1 inhibitor EX527 or ectopic expression of acetyl-mimetic (K33Q) CDK5 induced the opposite effect. Furthermore, the expression of nuclear-targeted CDK5 K33Q abolished the SRT1720-induced neurite outgrowth, showing that SIRT1 positively regulates neurite outgrowth via deacetylation of nuclear CDK5. The CDK5 activity-dependent increase of neurite length was mediated by enhanced transcriptional regulation of BDNF via unknown mechanism(s). Our findings identify a novel mechanism by which acetylation-mediated regulation of nuclear CDK5 activity plays a critical role in determining neurite length in embryonic neurons.",

author = "Juhyung Lee and Ko, {Yeon Uk} and Yuhyun Chung and Nuri Yun and Myungjin Kim and Kyungjin Kim and Oh, {Young J.}",

note = "Funding Information: This work was supported by the Mid-Career Research Program (NRF; 2017R1A2B4007301 to YJO), and by the Brain Research Program through the National Research Foundation of Korea (2017M3C7A1025369 to YJO). This research was supported in part by the NRF-2014R1A2A1A01003680 (to KK), and by the Basic Research Program through Korea Brain Research Institute (KBRI) funded by Ministry of Science and ICT (18-BR-02-01 to MK). YUK and YHC are recipients of the BK21 Plus. We are grateful to Dr. Ja-Eun Kim (Kyunghee University), Dr. Jason W. Chin (University of Cambridge), Dr. Hyunsook Lee (Seoul National University) and Dr. Jacques C{\^o}te (Laval University) for providing plasmids, to Dr. Eutteum Jeong (Ewha Womans University) for helping real-time PCR analysis, and to Dr. Dongeun Park (Seoul National University) for his advice on neurite outgrowth analysis. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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AU - Yun, Nuri

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AU - Kim, Kyungjin

AU - Oh, Young J.

N1 - Funding Information: This work was supported by the Mid-Career Research Program (NRF; 2017R1A2B4007301 to YJO), and by the Brain Research Program through the National Research Foundation of Korea (2017M3C7A1025369 to YJO). This research was supported in part by the NRF-2014R1A2A1A01003680 (to KK), and by the Basic Research Program through Korea Brain Research Institute (KBRI) funded by Ministry of Science and ICT (18-BR-02-01 to MK). YUK and YHC are recipients of the BK21 Plus. We are grateful to Dr. Ja-Eun Kim (Kyunghee University), Dr. Jason W. Chin (University of Cambridge), Dr. Hyunsook Lee (Seoul National University) and Dr. Jacques Côte (Laval University) for providing plasmids, to Dr. Eutteum Jeong (Ewha Womans University) for helping real-time PCR analysis, and to Dr. Dongeun Park (Seoul National University) for his advice on neurite outgrowth analysis. Publisher Copyright: © 2018, The Author(s).

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N2 - Cyclin-dependent kinase 5 (CDK5) plays a pivotal role in neural development and neurodegeneration. CDK5 activity can be regulated by posttranslational modifications, including phosphorylation and S-nitrosylation. In this study, we demonstrate a novel mechanism by which the acetylation of CDK5 at K33 (Ac-CDK5) results in the loss of ATP binding and impaired kinase activity. We identify GCN5 and SIRT1 as critical factor controlling Ac-CDK5 levels. Ac-CDK5 achieved its lowest levels in rat fetal brains but was dramatically increased during postnatal periods. Intriguingly, nuclear Ac-CDK5 levels negatively correlated with neurite length in embryonic hippocampal neurons. Either treatment with the SIRT1 activator SRT1720 or overexpression of SIRT1 leads to increases in neurite length, whereas SIRT1 inhibitor EX527 or ectopic expression of acetyl-mimetic (K33Q) CDK5 induced the opposite effect. Furthermore, the expression of nuclear-targeted CDK5 K33Q abolished the SRT1720-induced neurite outgrowth, showing that SIRT1 positively regulates neurite outgrowth via deacetylation of nuclear CDK5. The CDK5 activity-dependent increase of neurite length was mediated by enhanced transcriptional regulation of BDNF via unknown mechanism(s). Our findings identify a novel mechanism by which acetylation-mediated regulation of nuclear CDK5 activity plays a critical role in determining neurite length in embryonic neurons.

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The acetylation of cyclin-dependent kinase 5 at lysine 33 regulates kinase activity and neurite length in hippocampal neurons

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