|Institution||College of Medicine|
|Address||500 University Drive Hershey PA 17033|
Physician, Professor of Medicine, Co-Director of the MD/PhD Program, Co-Leader of the Penn State CTSI Pilot and Collaborative Translational and Clinical Studies
SECONDARY APPOINTMENT(S)/ INSTITUTE(S)/ CENTER(S):
Department of Microbiology and Immunology; Penn State Cancer Institute; Clinical and Translational Studies Institute; Graduate Faculty; Biomedical Sciences Faculty
GRADUATE PROGRAM AFFILIATIONS:
Biomedical Sciences, Cell and Molecular Biology, MD/PhD Degree Program, Microbiology and Immunology, Genetics
M.D., Duke University School of Medicine, 1987
Residency in Internal Medicine, Duke University Medical Center, 1989-1991
Fellowship in Infectious Diseases, Penn State College of Medicine, 1991-1994
Postdoctoral Training in Retrovirology, Penn State College of Medicine, 1992-1997
Overall goals: Our research centers around understanding the interactions between viruses and host cells at the molecular level. We use retroviruses as a model system to dissect molecular mechanisms of virus replication, which has led us to study the intracellular trafficking pathways of retroviral proteins and cellular factors that are recruited to facilitate virus propagation.
Retrovirus replication: The main structural proteins of the oncogenic retrovirus Rous sarcoma virus (RSV) are the Gag proteins, which are initially synthesized as a polyprotein precursor. The Gag polyprotein directs the assembly and budding of progeny retrovirus particles from the plasma membrane of infected cells. Gag proteins are synthesized on free ribosomes in the cytosol, and previously it was believed that they were then targeted directly to the plasma membrane. However, we discovered that the RSV Gag protein enters the nucleus using signals in the MA and NC domains for nuclear targeting. Gag proteins are exported out of the nucleus through the nuclear pore complex via the cellular exportin CRM-1 pathway and an interaction with the nuclear pore complex proteins Nup98 and Nup214. After nuclear export, Gag proteins form multimeric complexes bound to viral RNA. The assembling virus particles are targeted to the plasma membrane where they interact with cellular machinery to allow budding of nascent virions.
One of our main goals is to understand what role Gag proteins play in the nucleus. Collectively, our data suggest that the RSV Gag polyprotein enters the nucleus to interact with the unspliced viral RNA to initiate the genome encapsidation process. Our data support a model in which (i) Gag binds as a monomer to nuclear import factors (importin-11, transportin-SR, and importin alpha/beta) for nuclear entry, (ii) Gag binds to the viral genome in the nucleus, oligomerizes, and undergoes a conformational change that exposes its nuclear export signal in the p10 domain to facilitate binding of CRM1/RanGTP, (iii) Gag-viral RNA complexes are exported from the nucleus and traffic to the plasma membrane using host transport factors. This model represents a novel paradigm for how retroviruses select and package their genomes.
We use genetic, biochemical, biophysical, and dynamic live cell imaging approaches to dissect the mechanisms that control the trafficking of retroviruses in infected cells. By identifying the signals and host factors involved in transport of retroviral proteins and RNAs through different subcellular compartments, our research interfaces with basic questions in cellular biology.
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