Yan Yuan
Associate Professor, Dept of Microbiology

Microbiology, Virology and Parasitology Program

Address

248 Levy Research Building
4010 Locust St
Philadelphia, PA 19104

Office tel.: 215 573-7556
Lab tel.: 215 573-4221
Fax: 215 898-8385
E-mail: yuan2@pobox.upenn.edu


Education

Shandong University: BSc (Microbiology), 1982.

Shanghai Institute of Cell Biology, Academia Sinica: MSc (Cell Biology), 1985.

Baylor College of Medicine: PhD (Biochemistry and Molecular Biology), 1991.

Research Interests

• Kaposi's sarcoma-associated herpesvirus.

Key words Kaposi's sarcoma-associated herpesvirus, virus-host interaction, the external guide sequence technique.

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Description of Research

Kaposi's sarcoma-associated herpesvirus (KSHV) is a newly-identified human herpesvirus and an emerging pathogen. Increasing evidence indicate that this virus is the etiologic agent of Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD), leading neoplasia of AIDS patients. Unique among all DNA tumor viruses, KSHV lytic replication contributes significantly to the formation of KS lesions by either facilitating viral spread to the target site or releasing paracrine factors to support the growth of KS tumor cells. Therefore, KSHV reactivation from latency to lytic replication is not only important for viral propagation, but also critical for viral pathogenicity. My laboratory has been interested in the mechanisms used by KSHV to switch from latency to lytic life cycle. In the past a few years, several major accomplishments have been achieved. (1) Several KSHV immediate-early (IE) genes have been identified in our lab. Since the reactivation process is controlled and regulated by viral immediate-early gene products, identification of the IE genes has opened an avenue towards revelation of the mechanisms underlying KSHV infection and reactivation. The functional roles of these IE proteins have begun to be unraveled. ORF50 was found to be a transcriptional activator, able to activate viral lytic genes; ORF45 was shown to be a protein that the virus uses to subvert interferon-related host antiviral defenses. (2) Recently, we identified two origins of lytic DNA replication (ori-Lyt) in the KSHV genome and two origin binding proteins (K8 and ORF50). These discoveries will allow the study of the regulation of KSHV lytic DNA replication. (3) Mature KSHV particles were purified and virion components were identified by using proteomic approaches including an HPLC ion trap mass spectrometic (LC-MS/MS) analysis. Twenty-four viral proteins and many cellular proteins were identified in KSHV virions.

Currently, the research in my lab is following up those lines of investigation that were successfully developed over the past several years and aim at the following issues.

1. We will continue to investigate the roles of immediate-early proteins ORF50 and ORF45 in KSHV replication and pathogenicity. In particular, ORF45 inhibits virus-induced interferon production by blocking IRF-7 phosphorylation and nuclear translocation. This protein is not only expressed with immediate-early kinetics, but is also packaged into infectious virions. Our hypothesis is that ORF45 has crucial roles in both initial infection process and viral reactivation.
2. We will analyze the structure and function of KSHV ori-Lyt and investigating the role of the ori-Lyt binding proteins K8 and ORF50 in the regulation of KSHV lytic DNA replication. Furthermore, a number of cellular proteins have recently been identified in the KSHV lytic replication complex in our lab using a proteomic approach. The data suggest that the viral lytic replication requires association of an ori-Lyt with nuclear matrix and is coupled with transcription events. Thus, we will study the regulation of viral DNA replication in different levels including nuclear skeleton, chromatin structure and interplay between DNA replication and transcription.
3. Virion proteins are believed to contain the functional information for virion assembly and de novo infection. Identification of the entire repertoire of KSHV virion proteins made it possible to reveal the roles of these virion proteins in viral life cycle. We will employ a new strategy to study roles of KSHV virion proteins in viral life cycle and pathogenicity. Instead of defining the functional role of each virion protein, we will first generate a virion-wide protein-protein interaction map of KSHV by cloning each of virion proteins and examining possible interaction between any two proteins using yeast two hybrid method. Based on the result, functional role of each tegument proteins will be predicted and then studied through analyzing recombinant mutant viruses. In addition, the structure of tegument of KSHV will be investigated using cryo-electron microscopy (cryo-EM) in collaboration with Dr. Zhou lab at University of Texas Houston Medical School.
   Overall, through the studies in these three directions, we will gain insights into the mechanisms that control KSHV infection and reactivation, that will shed light on the pathogenesis of KS and other KSHV-associated diseases.
   

Recent Publications

Zhu, F. X., Chong, J. M., Wu, L. and Yuan, Y. (2005) Virion Proteins of Kaposi’s Sarcoma-associated Herpesvirus. J. Virol. 79:800-811.

Wang, Y., Li, H., Chan, M. Y., Lukac, D. M. and Yuan, Y. (2004) Kaposi’s Sarcoma-Associated Herpesvirus ori-Lyt-dependent DNA Replication: cis-acting Requirements for the replication and ori-Lyt-associated RNA transcription. J. Virol. 78:8615-8629.

Lin, C., Li, H., Wang, Y, Kudchodkar, S., Zhu, F. X. and Yuan, Y. (2003) Kaposi's sarcoma-associated herpesvirus ori-Lyt-dependent DNA replication: Identification of the ori-Lyt and association of K8 bZip protein with the origin. J. Virol. 77:5578-5588.

Zhu, F. X., King, S. M., Smith, E. J., Levy, D. E. and Yuan, Y. (2002) A Kaposi's Sarcoma-associated Herpesviral protein inhibits virus-mediated induction of type I interferon by blocking IRF-7 phosphorylation and nuclear accumulation. Proc. Natl. Acad. Sci. USA 99:5573-5578.

Zhu, F. X., Cusano, T. and Yuan, Y. (1999) Identification of the immediate early transcripts of Kaposi's sarcoma associated herpesvirus. J. Virol. 73: 5556-5567.
Lab

Lab

Rotation Projects for 2006-2007

1. Mechanism of inactivation of IRF-7 by KSHV ORF45.
2. Cis- and trans-acting elements for KSHV lytic DNA replication.
3. Structure and function of KSHV tegument proteins.
   

Lab personnel:

Fanxiu Zhu, Ph.D. – Research Scientist
Yan Wang, Ph. D. – Postdoctoral Associate
Ramona Rozen, Ph.D. – Postdoctoral Associate
Sathish Narayanan, Ph.D. – Postdoctoral Associate