Director, Montana Biotechnology Center
The virus envelope glycoprotein orchestrates entry of the virus into its target cell by mediating attachment to cell-surface receptors and fusion of the virus and cell membranes. As such, these glycoproteins provide fertile ground for study towards the development of antiviral agents and vaccines. My laboratory is interested in cellular, molecular, and structural aspects of virus assembly and entry.
The recent focus of my lab has been on the envelope glycoprotein (GPC) of the Arenaviruses, a little-studied family of rodent-borne viruses responsible for hemorrhagic fevers worldwide (Lassa fever in Africa, and South American hemorrhagic fevers in the New World). Over the past several years, we have characterized the unusual GPC complex. In addition to the receptor-binding and transmembrane fusion subunits common to all Class I envelope glycoproteins, GPC retains a cleaved and stable signal peptide (SSP) as an essential element. On the cytoplasmic face of GPC, SSP likely forms an intersubunit zinc-finger structure with the transmembrane subunit and functions in intracellular transport of GPC to the cell surface, and in virion assembly. The ectodomain of SSP interacts with the ectodomain of the transmembrane fusion subunit to modulate low pH-induced activation of membrane fusion, which takes place in the maturing endosome of the cell. Genetic and structural studies are underway to define the role of this pH-sensitive interface in membrane fusion, and the basis for fusion inhibition by structurally diverse small-molecule antiviral compounds.
A.B. Cornell University, 1972
Ph.D. Stanford University, 1979
York J, Dai D, Amberg SM, Nunberg JH. (2008) pH-induced activation of arenavirus membrane fusion is antagonized by small-molecule inhibitors. J Virol. [Epub ahead of print]
Lee AM, Rojek JM, Spiropoulou CF, Gundersen AT, Jin W, Shaginian A, York J, Nunberg JH, Boger DL, Oldstone MB, Kunz S. (2008) Unique small molecule entry inhibitors of hemorrhagic fever arenaviruses. J Biol Chem. 283:18734-42.
York J, Nunberg JH. (2007) A novel zinc-binding domain is essential for formation of the functional Junín virus envelope glycoprotein complex.J Virol. 81:13385-91.
Radoshitzky SR, Abraham J, Spiropoulou CF, Kuhn JH, Nguyen D, Li W, Nagel J, Schmidt PJ, Nunberg JH, Andrews NC, Farzan M, Choe H. (2007) Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses. Nature 446:92-6.
Agnihothram SS, York J, Trahey M, Nunberg JH. (2007) Bitopic membrane topology of the stable signal peptide in the tripartite Junín virus GP-C envelope glycoprotein complex. J Virol. 81:4331-7.
York J, Nunberg JH. (2007) Distinct requirements for signal peptidase processing and function in the stable signal peptide subunit of the Junín virus envelope glycoprotein. Virology 359:72-81.
York J, Nunberg JH. (2006) Role of the stable signal peptide of Junín arenavirus envelope glycoprotein in pH-dependent membrane fusion. J Virol. 80:7775-80.
Agnihothram SS, York J, Nunberg JH. (2006) Role of the stable signal peptide and cytoplasmic domain of G2 in regulating intracellular transport of the Junín virus envelope glycoprotein complex. J Virol. 80:5189-98.