A breakthrough in EBV research could lead to advance understanding of the virus mediated tumorigenesis
Dr. Chih-Wen Peng, Professor at the Institute of Medical Sciences Tzu Chi University, and his colleagues recently made an remarkable achievement in viral oncology research by unraveling the mechanistic profile of the RPL4/NCL scaffold in Epstein-Barr Virus nuclear antigen 1 (EBNA1) mediated viral latency-associated events that is known to be linked to EBV-induced tumorigenesis. The research work was published in the reputable journal Proc Natl Acad Sci USA on Feb. 23, 2016 (1). Moreover, the collaboration of Dr. Peng with Dr. Jikui Song at the Biochemistry Department University of California, Riverside led to discover a novel phenomenon of EBV and host interaction upon virus infection within the infected cells. This study revealed a transcription repressor BS69 participates in the process of host defense to EBV through targeting to nuclear antigen 2 (EBNA2). The research work was published in the top ranking pathological journal PLOS pathogens on Feb. 6, 2016 (2). The Ph. D. students Cheng-Der Liu and Chih-Lung Shen from the Institute of Medical Sciences are the key persons to be involved in two research projects. These findings not only deliver a breakthrough in EBV research but also open a new way for future anti-EBV drug discovery.
Since the discovery of Epstein-Barr virus (EBV) 50 years ago, the etiologic links between EBV and a variety of human cancers have gained wide recognition. It is estimated that more than 90% of the worldwide population become the carriers of this virus, which causes over 200,000 cancers across the world every year. EBNA1 and EBNA2 are two key proteins in driving immortalization of EBV infected B cells, which regulates the expression of many cellular and viral genes. Both viral oncogenes are implicated in EBV-related malignancies with their essential role in the maintenance of the permanent EBV infection in human B cells. The maintenance of the EBV genome and viral gene expression from the episome are specifically driven by EBNA1 through binding to origin of plasmid replication (oriP). Dr. Peng’s team finds that EBNA1 complexes with Ribosome Protein L4 (RPL4) and Nucleolin (NCL) to stabilize EBNA1 binding to oriP. Cooperation of RPL4’s N terminus with NCL K429 is necessary for EBNA1 oriP binding and episome maintenance, whereas RPL4’s C-terminal K380 and K393 induce H3K4me2, which promotes EBNA1 transactivation of oriP.
The collaboration work of Dr. Peng, Dr. Song, and colleagues unravel the crystal structure of the coiled-coil and MYND tandem domains of BS69/ZMYND11, a candidate tumor suppressor, in complex with an EBNA2 peptide containing a PXLXP motif. They found that the coiled-coil and MYND domains of BS69 cooperate in binding to EBNA2, which is recruited to viral target promoters and through interaction with EBNA2. Of importance, the shutoff of BS69 expression by EBNA2 in EBV infected cells counters the host defense route. Taken together, these discoveries enhance our understanding of the complexity of EBNA1’s or EBNA2’s interactions with host proteins and reveal new targets for future drug development for EBV associated malignancies.
1. The full article is entitled “Ribosome Protein L4 is essential for Epstein–Barr
Virus Nuclear Antigen 1 function” and is available at the Proc Natl Acad Sci USA web site at: http://www.pnas.org/content/113/8/2229.
2. The full article is entitled “BS69/ZMYND11 C-Terminal Domains Bind and Inhibit EBNA2” and is available at the PLOS Pathogens web site at: http:// http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005414.
Dr. Chih-Wen Peng, Professor, Institute of Biomedical Sciences, Tzu Chi University. email@example.com (Tel) 886-3-856-2926