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Joseph Pagano

Joseph Pagano

Area of Interest

The Epstein-Barr Virus (EBV) is associated with malignancies of lymphocytic and epithelial origin. EBV produces different infection states, cytolytic and latent, as well as cell immortalization, all of which are captured in cell lines, making the different states accessible to mechanistic studies. Recently we have access to a humanized mouse model (see Lishan Su, http://unclineberger.org) for EBV infection and transformation studies. Currently our research deals with viral latency, functions of the EBV protein kinase and deubiquitinating enzymes in EBV systems, interferon regulatory factors (IRFs), invasion and metastasis induced by the EBV oncoprotein LMP1, and antiviral drugs.

In EBV's cytolytic infection cycle we are focusing on two EBV gene products. One encodes EBV's sole protein kinase which phosphorylates at least 20 EBV proteins, including the EBV DNA polymerase processivity factor used in viral replication, viral maturation proteins involved in egress of viral nucleocapids from the nucleus, and the R1 subunit of the EBV ribonucleotide reductase (RR). The other gene encodes the EBV deubiquitinating enzyme (DUB), which down-regulates function of the EBV RR, the first target identified for herpesvirus DUBs.

We also study mechanisms of cell immortalization and oncogenesis through EBV's ability to stabilize and activate β-catenin via the ubiquitin system with the focus on the cellular deubiquitinating enzyme, UCH L1. This DUB is induced by the master transcriptional transactivator, EBNA2, in EBV-transformed cells. Recently we discovered that UCH L1 is expressed in association with the mitotic spindle and regulates microtubule dynamics in diverse transformed cells.

IRF7 was discovered in this laboratory. How EBV is able to mount and evade IRF7-mediated immune responses, and the ability of EBV LMP1 to induce and activate IRF7, now recognized as the master regulator of type I interferon responses, through ubiquitination remain principal focuses.

Finally we hold that EBV, in addition to being an etiologic agent for its associated malignancies, may also serve to promote tumor progression. EBV’s major oncoprotein LMP1 can induce epithelial-mesenchymal transition (EMT) and promote cell migration through up-regulation of invasion, metastasis and angiogenic factors in NPC, as shown recently with Twist and Snail transcription factors and through phosphorylation of the ERM family member, Ezrin.

All trainees are encouraged to broaden their experience by also participating in the well known UNC-LCCC Postdoctoral Training Program, now in its 35th year, to assist in reaching their career goals. Fellows in my laboratory also present work in progress at the weekly meetings of the Virology Faculty at UNC.

Awards and Honors

Recent discoveries:

•The neuronal protein UCH L1 is aberrantly expressed in a variety of carcinomas and lymphomas. We have discovered a fundamental function for this ubiquitin-editing enzyme: its deubiquitinating and ubiquitin ligase activities are associated with tubulin throughout mitosis and affect its polymerization.

•LMP1, the principal oncoprotein of EBV, activates IRF7 through a RIP- and TRAF6-dependent ubiquitination pathway.

•A tumor virus, EBV, can activate the β-catenin signaling pathway in human lymphocytes through a novel mechanism, induction of the deubiquitinating enzyme UCH L1.

• IRF-7 has oncogenic properties that may potentiate those of LMP-1.

•Twist, a transcriptional factor essential for breast cancer metastasis and epithelial-mesenchymal transition, is detected with LMP1 in nasopharyngeal carcinoma.

•Phosphorylation of Ezrin, a member of the ERM family that links plasma membrane and the actin cytoskeleton and drives cell immigration, is induced by LMP1 and detected in nasopharyngeal carcinoma.

•The antiviral drug Maribavir in contrast to Acyclovir inhibits not only viral replication but viral transcription.

Honors:
2004 Fellow, American Association for the Advancement of Science
2009- Member, Science Advisory Board, US Food & Drug Administration