Phosphorylation of p27Kip1 by epstein-barr virus protein kinase induces its degradation through SCFSkp2 ubiquitinligase actions during viral lytic replication

Satoko Iwahori, Takayuki Murata, Ayumi Kudoh, Yoshitaka Sato, Sanae Nakayama, Hiroki Isomura, Teru Kanda, Tatsuya Tsurumi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Epstein-Barr virus (EBV) productive replication occurs in an S-phase-like cellular environment with high cyclin-dependent kinase (CDK) activity. The EBV protein kinase (PK), encoded by the viral BGLF4 gene, is a Ser/Thr protein kinase, which phosphorylates both viral and cellular proteins, modifying the cellular environment for efficient viral productive replication. We here provide evidence that the EBV PK phosphorylates the CDK inhibitor p27Kip1, resulting in ubiquitination and degradation in a proteasome-dependent manner during EBV productive replication. Experiments with BGLF4 knockdown by small interfering RNA and BGLF4 knock-out viruses clarified that EBV PK is involved in p27Kip1 degradation upon lytic replication. Transfection of the BGLF4 expression vector revealed that EBV PK alone could phosphorylate the Thr-187 residue of p27Kip1 and that the ubiquitination and degradation of p27Kip1 occurred in an SCFSkp2 ubiquitin ligase-dependent manner. In vitro, EBV PK proved capable of phosphorylating p27Kip1 at Thr-187. Unlike cyclin E-CDK2 activity, the EBV PK activity was not inhibited by p27Kip1. Overall, EBV PK enhances p27Kip1 degradation effectively upon EBV productive replication, contributing to establishment of an S-phase-like cellular environment with high CDK activity.

Original languageEnglish
Pages (from-to)18923-18931
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number28
DOIs
Publication statusPublished - 10-07-2009

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Phosphorylation
Human Herpesvirus 4
Viruses
Protein Kinases
Degradation
Cyclin-Dependent Kinases
Virus Replication
Ubiquitination
S Phase
Cyclin E
Viral Genes
Viral Proteins
Proteasome Endopeptidase Complex
Ligases
Ubiquitin
Corrosion inhibitors
Small Interfering RNA
Transfection
Genes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Iwahori, Satoko ; Murata, Takayuki ; Kudoh, Ayumi ; Sato, Yoshitaka ; Nakayama, Sanae ; Isomura, Hiroki ; Kanda, Teru ; Tsurumi, Tatsuya. / Phosphorylation of p27Kip1 by epstein-barr virus protein kinase induces its degradation through SCFSkp2 ubiquitinligase actions during viral lytic replication. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 28. pp. 18923-18931.
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abstract = "Epstein-Barr virus (EBV) productive replication occurs in an S-phase-like cellular environment with high cyclin-dependent kinase (CDK) activity. The EBV protein kinase (PK), encoded by the viral BGLF4 gene, is a Ser/Thr protein kinase, which phosphorylates both viral and cellular proteins, modifying the cellular environment for efficient viral productive replication. We here provide evidence that the EBV PK phosphorylates the CDK inhibitor p27Kip1, resulting in ubiquitination and degradation in a proteasome-dependent manner during EBV productive replication. Experiments with BGLF4 knockdown by small interfering RNA and BGLF4 knock-out viruses clarified that EBV PK is involved in p27Kip1 degradation upon lytic replication. Transfection of the BGLF4 expression vector revealed that EBV PK alone could phosphorylate the Thr-187 residue of p27Kip1 and that the ubiquitination and degradation of p27Kip1 occurred in an SCFSkp2 ubiquitin ligase-dependent manner. In vitro, EBV PK proved capable of phosphorylating p27Kip1 at Thr-187. Unlike cyclin E-CDK2 activity, the EBV PK activity was not inhibited by p27Kip1. Overall, EBV PK enhances p27Kip1 degradation effectively upon EBV productive replication, contributing to establishment of an S-phase-like cellular environment with high CDK activity.",
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Phosphorylation of p27Kip1 by epstein-barr virus protein kinase induces its degradation through SCFSkp2 ubiquitinligase actions during viral lytic replication. / Iwahori, Satoko; Murata, Takayuki; Kudoh, Ayumi; Sato, Yoshitaka; Nakayama, Sanae; Isomura, Hiroki; Kanda, Teru; Tsurumi, Tatsuya.

In: Journal of Biological Chemistry, Vol. 284, No. 28, 10.07.2009, p. 18923-18931.

Research output: Contribution to journalArticle

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AU - Iwahori, Satoko

AU - Murata, Takayuki

AU - Kudoh, Ayumi

AU - Sato, Yoshitaka

AU - Nakayama, Sanae

AU - Isomura, Hiroki

AU - Kanda, Teru

AU - Tsurumi, Tatsuya

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