Degradation of Phosphorylated p53 by Viral Protein-ECS E3 Ligase Complex

PLoS Pathogens

Tatsuya Tsurumi¹  Takumi Kamura¹  Noriko Shirata²  Sanae Nakayama³  Ayumi Kudoh³  Yoshitaka Sato³  Satoko Iwahori³  Hiroki Isomura³  Yukihiro Nishiyama³  Takayuki Murata³ 

[1] Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan;Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Japan;Division of Virology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan

关键词: Ubiquitination;    Immunoprecipitation;    Phosphorylation;    DNA-binding proteins;    Plasmid construction;    Epstein-Barr virus;    Ligases;    Ubiquitin ligases;   

DOI  :  10.1371/journal.ppat.1000530

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

p53-signaling is modulated by viruses to establish a host cellular environment advantageous for their propagation. The Epstein-Barr virus (EBV) lytic program induces phosphorylation of p53, which prevents interaction with MDM2. Here, we show that induction of EBV lytic program leads to degradation of p53 via an ubiquitin-proteasome pathway independent of MDM2. The BZLF1 protein directly functions as an adaptor component of the ECS (Elongin B/C-Cul2/5-SOCS-box protein) ubiquitin ligase complex targeting p53 for degradation. Intringuingly, C-terminal phosphorylation of p53 resulting from activated DNA damage response by viral lytic replication enhances its binding to BZLF1 protein. Purified BZLF1 protein-associated ECS could be shown to catalyze ubiquitination of phospho-mimetic p53 more efficiently than the wild-type in vitro. The compensation of p53 at middle and late stages of the lytic infection inhibits viral DNA replication and production during lytic infection, suggesting that the degradation of p53 is required for efficient viral propagation. Taken together, these findings demonstrate a role for the BZLF1 protein-associated ECS ligase complex in regulation of p53 phosphorylated by activated DNA damage signaling during viral lytic infection.

【 授权许可】

CC BY