Study on EBV induced pathogenesis under the scope of virus-host interaction

• Main Authors: Cheng-Der Liu, 劉政德
• Other Authors: Chih-Wen Peng
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/9tkj67

博士 === 慈濟大學 === 醫學科學研究所 === 106 === Epstein-Barr Virus (EBV) is a well-defined oncogenic γ-human herpesvirus. Understanding of the mechanism of EBV mediated cellular transformation is an important necessity for researchers to understand the role of EBV in tumorigenesis and to develop potential therapeutic protocols for EBV-associated malignancies. Both EBNA1 and EBNA2 are key factors that are involved in the establishment and maintenance of EBV permanent infection in host cells. EBNA1 is the only viral protein to be expressed in all forms of latency in EBV-associated diseases. EBNA1 plays multiple roles at the EBV episome during latent infection, including maintenance, replication, and mitotic segregation of the EBV genome, whereas EBNA2 is known to trigger transcription activation through interactions with cellular DNA-binding proteins. During the past five years, my research work mainly focused on exploring the working model by which EBNA1 or EBNA2 recruits cellular factors through protein-protein interaction networks to support the establishment and maintenance of EBV latent infection in host B cells. My recent findings highlighted the essential role of nucleophosmin (NPM1) in chaperoning EBNA2 onto the latency-associated membrane protein 1 promoter, which is coordinated with the subsequent activation of transcriptional cascades through interactions with RBP-J during EBV infection. The ATP-bound state of NPM1 was then identified as the key player in the formation of EBNA2/RBP-J induced transcription pre-initiation complex. Yet another research work demonstrated that PRMT5 substantially interacts with an EBNA2 ariginine-glycine rich domain and mediates the symmetric methylation of the ariginine residues, subsequently leads to promote EBNA2 binding to the cognate elements thereby upregulating of the latency-associated transcriptional program. This research work points to an importance of PRMT5 in supporting the establishment of EBV permanent infection in host cells. My recent collaboration work with Dr. Jikui Song, Department of Biochemistry University of California, Riverside, has led to 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. This part of my research work provides important data to suggest that BS69 MYND could potentially trigger an anti-EBV defensive event through down regulation of EBNA2-dependent transcription. Finally, my recent study demonstrates that the ATP bound state of nucleolin acts as an EBNA1 scaffold to induce complex formation at viral DNA to sustain the persistence of EBV episome. NCL RNA-binding domain K429 is shown critical for both ATP and EBNA1 binding. Taken together, the overall studies shed new light on our understanding of the complexity by which EBV exploits or subverts host factors to establish permanent infection in host cells thereby identifying new potential targets for future drug development of EBV-associated malignancies.