associate professor of biology
Ph.D., Rockefeller University
Fields of Interest
Nuclear import and export of viral and cellular macromolecules.
The basic paradigm for nuclear import is that a protein containing a nuclear localization signal (NLS) interacts directly, or via an adapter, with an import receptor belonging to the karyopherin beta/importin beta (Kap beta/Imp beta) superfamily, is translocated through the nuclear pore complex and released in the nucleus. We had previously identified and characterized several nuclear import pathways for proteins containing a classical nuclear localization signal, for hnRNP A1 and for Influenza virus RNA.
My current research program focuses on the identification and characterization of the nuclear import pathways for the proteins and DNA of human papillomaviruses (HPVs). More than 100 HPV genotypes have been isolated and characterized, with roughly half infecting the skin and the other half the oral/anogenital mucosal epithelial tissues. Mucosal HPVs have demonstrated varying degrees of oncogenic potential. High risk HPVs, such as types 16, 18 and 45, are frequently detected in invasive cervical carcinomas. Low risk HPVs, such as types 6 and 11, are more often associated with benign exophytic condylomas. HPVs are small, nonenveloped, icosahedral DNA viruses that infect squamous epithelial cells. The virion particles (52-55 nm in diameter) consist of a single molecule of 8 kb double-stranded circular DNA contained within a spherical capsid composed of 72 homopentameric L1 capsomeres and 12 molecules of L2 minor capsid protein. During the late phase of viral infection, HPV L1 major capsid proteins enter the nuclei of terminally differentiated epithelial cells and, together with the L2 minor capsid proteins, assemble the viral DNA into virions.
Nuclear import and export of HPV proteins and nucleic acids are crucial for the viral life cycle and pathogenesis. Projects in my lab include: identification and characterization of the nuclear import pathways for L1 and L2 capsid proteins and for E6 and E7 oncoproteins of both high and low risk HPVs; the molecular mechanisms for nuclear import of HPV genomic DNA; and nuclear export pathways for E6 oncoproteins and viral transcripts. Our studies defining the transport pathways for HPV proteins and nucleic acids will make a significant contribution to the understanding of the HPV life cycle and pathogenesis.
Piccioli, Z., McKee, C.H., Leszczynski, A., Onder, Z., Hannah, C.H., Mamoor, S., Crosby, L., and Moroianu, J. 2010. The Nuclear Localization of Low Risk HPV11 E7 Protein Mediated by its Zinc Binding Domain Is Independent of Nuclear Import Receptors. Virology, 407:100-109.
Knapp, A. A., McManus P. M., Bockstall, K., and Moroianu, J. 2009. Identification of the nuclear localization and export signals of high risk HPV16 E7 oncoprotein. Virology 383(1): 60–8.
Bird, G., O’Donnell, M., Moroianu, J., Garcea, R.L. 2008. Possible role for cellular karyopherins in regulating polyomavirus and papillomavirus capsid assembly. Journal of Virology 82(20): 9848–9857 (selected by the editors for the Spotlight, highlighting articles of significant interest).
Klucevsek, K., Wertz, M., Lucchi, J., Leszczynski, A., and Moroianu, J. 2007. Characterization of the nuclear localization signal of high risk HPV16 E2 protein. Virology 360(1): 191–198.
Bordeaux, J., Forte, S., Darshan, M.S., Harding, E., Klucevsek, K., and Moroianu, J. 2006. The L2 minor capsid protein of low risk human papillomavirus type 11 interacts with host nuclear import receptors and viral DNA. Journal of Virology 80(16): 8259–8262.
Klucevsek, K., Daley, J., Darshan, M.S., Bordeaux, J., and Moroianu, J. 2006. Nuclear import strategies of high risk HPV18 L2 minor capsid protein. Virology 352(1): 200–208.
Fay, A., Yutzy, W. H. IV, Roden, R. B., and Moroianu, J. 2004. The positively charged termini of L2 minor capsid protein required for bovine papillomavirus infection function separately in nuclear import and DNA binding. Journal of Virology 78: 13447–13454.
Darshan, M. S., Lucchi, J., Harding E., and Moroianu, J. 2004. The L2 minor capsid protein of human papillomavirus type 16 interacts with a network of nuclear import receptors. Journal of Virology 78: 12179–12188.
Angeline, M., Merle, E., Moroianu, J. 2003. The E7 oncoprotein of high risk human papillomavirus type 16 enters the nucleus via a nonclassical ran-dependent pathway. Virology 317: 13–23.
Nelson, L. M., Rose, R.C., and Moroianu, J. 2003. The L1 major capsid protein of human papillomavirus type 11 interacts with Kap ß2 and Kap ß3 nuclear import receptors. Virology 306: 162–169.
LeRoux, L., and Moroianu, J. 2003. Nuclear entry of high risk HPV16 E6 oncoprotein occurs via several pathways. Journal of Virology 77(4): 2330–2337.
Nelson, L.M., Rose, R.C., Moroianu, J. 2002. Nuclear import strategies of high risk HPV16 L1 major capsid protein. Journal of Biological Chemistry 277: 23958–23964.
Nelson, L.M., Rose, R.C., LeRoux, L., Lane, C., Bruya, K., Moroianu, J. 2000. Nuclear import and DNA binding of human papillomavirus type 45 L1 capsid protein. Journal of Cellular Biochemistry 79: 225–238.
Merle, E., Rose, R.C., LeRoux, L., Moroianu, J. 1999. Nuclear import of HPV11 L1 capsid protein is mediated by karyopherin alpha 2/beta1 heterodimers. Journal of Cellular Biochemistry 74: 628–637.
Moroianu, J. 1999. Nuclear import and export pathways. Journal of Cellular Biochemistry. Supplement 32/33: 76–83.
Moroianu, J. 1999. Nuclear import and export: Transport factors, mechanisms and regulation. Critical Reviews in Eukaryotic Gene Expression 9(2): 89–106.
Bonifaci, N., Moroianu, J., Radu, A., and Blobel, G. 1997. Karyopherin beta2 mediates nuclear import of a mRNA binding protein. Proceedings of the National Academy of Sciences of the USA 94: 5055–5060.
O'Neill, R. E., Jaskunas, R., Blobel, G., Palese, P., and Moroianu, J. 1995. Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import. Journal of Biological Chemistry 270: 22701–22704.
Moroianu, J., Hijikata, M., Blobel, G., and Radu, A. 1995. Mammalian karyopherin alpha1 and alpha2 heterodimers: alpha1 or alpha2 subunits bind nuclear localization signal and beta subunit interacts with peptide repeat-containing nucleoporins. Proceedings of the National Academy of Sciences of the USA 92: 6532–6536.