The Nuclear Chaperone Nucleophosmin Escorts an Epstein-Barr Virus Nuclear Antigen to Establish Transcriptional Cascades for Latent Infection in Human B Cells
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Liu, Cheng-Der
Cheng, Chi-Ping
Chen, Ya-Lin
Min, Yi-Li
Kang, Myung-Soo
Chiu, Shu-Jun
Peng, Chih-Wen
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https://doi.org/10.1371/journal.ppat.1003084Metadata
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Liu, Cheng-Der, Ya-Lin Chen, Yi-Li Min, Bo Zhao, Chi-Ping Cheng, Myung-Soo Kang, Shu-Jun Chiu, Elliott D. Kieff, and Chih-Wen Peng. 2012. The nuclear chaperone nucleophosmin escorts an Epstein-Barr virus nuclear antigen to establish transcriptional cascades for latent infection in human B cells. PLoS Pathogens 8(12): e1003084.Abstract
Epstein-Barr Virus (EBV) is an oncogenic γ-herpesvirus that capably establishes both latent and lytic modes of infection in host cells and causes malignant diseases in humans. Nuclear antigen 2 (EBNA2)-mediated transcription of both cellular and viral genes is essential for the establishment and maintenance of the EBV latency program in B lymphocytes. Here, we employed a protein affinity pull-down and LC-MS/MS analysis to identify nucleophosmin (NPM1) as one of the cellular proteins bound to EBNA2. Additionally, the specific domains that are responsible for protein-protein interactions were characterized as EBNA2 residues 300 to 360 and the oligomerization domain (OD) of NPM1. As in c-MYC, dramatic NPM1 expression was induced in EBV positively infected B cells after three days of viral infection, and both EBNA2 and EBNALP were implicated in the transactivation of the NPM1 promoter. Depletion of NPM1 with the lentivirus-expressed short-hairpin RNAs (shRNAs) effectively abrogated EBNA2-dependent transcription and transformation outgrowth of lymphoblastoid cells. Notably, the ATP-bound state of NPM1 was required to induce assembly of a protein complex containing EBNA2, RBP-Jκ, and NPM1 by stabilizing the interaction of EBNA2 with RBP-Jκ. In a NPM1-knockdown cell line, we demonstrated that an EBNA2-mediated transcription defect was fully restored by the ectopic expression of NPM1. Our findings highlight the essential role of NPM1 in chaperoning EBNA2 onto the latency-associated membrane protein 1 (LMP1) promoters, which is coordinated with the subsequent activation of transcriptional cascades through RBP-Jκ during EBV infection. These data advance our understanding of EBV pathology and further imply that NPM1 can be exploited as a therapeutic target for EBV-associated diseases.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521654/pdf/Terms of Use
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