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 Jun Oh

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 languageEnglish
Article number13676
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Cyclin-Dependent Kinase 5
Neurites
Acetylation
Lysine
Phosphotransferases
Neurons
Brain-Derived Neurotrophic Factor
Post Translational Protein Processing

All Science Journal Classification (ASJC) codes

  • General

Cite this

Lee, Juhyung ; Ko, Yeon Uk ; Chung, Yuhyun ; Yun, Nuri ; Kim, Myungjin ; Kim, Kyungjin ; Oh, Young Jun. / The acetylation of cyclin-dependent kinase 5 at lysine 33 regulates kinase activity and neurite length in hippocampal neurons. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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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.",
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The acetylation of cyclin-dependent kinase 5 at lysine 33 regulates kinase activity and neurite length in hippocampal neurons. / Lee, Juhyung; Ko, Yeon Uk; Chung, Yuhyun; Yun, Nuri; Kim, Myungjin; Kim, Kyungjin; Oh, Young Jun.

In: Scientific reports, Vol. 8, No. 1, 13676, 01.12.2018.

Research output: Contribution to journalArticle

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