Functional studies of protein-protein interactions between flavivirus and the host cell

Flavivirus NS5 is an RNA dependent RNA polymerase essential for the virus life cycle. NS5 is also a flaviviral virulence factor as the protein affect and block parts of the innate immune response during viral infection.

This project reveals and characterizes novel protein-protein interactions between NS5 and the host cell. These interactions are connected to processes important for the understanding of disease outcome and replication of the virus.  We have shown that the TBE virus controls its mammalian host as NS5 specifically inhibit the type 1 interferon (IFN α/β) induced JAK-STAT pathway. By mapping the binding between NS5 and the PDZ protein Scribble we showed that the binding affects cell polarization induced by neuronal growth factor. We have recently discovered that the West Nile virus NS5 interacts with the PDZ protein found in the host cell mitochondria. Mitochondria have important functions for the cellular immune response, and we are characterizing these interactions and putative connections to innate immunity and apoptosis. We have developed several flavivirus replicon models, which are studied in different types of cells. In addition we have constructed systems for reverse genetics of TBE in collaboration with Anna Överby (Umeå University). Generated knowledge about flaviviral interactions with the host cell and the host immune response will be used for design of antivirals for future specific disease treatment.

More information Developvaccines@oru

Publications

Wigerius, M., Asghar, N., Melik, W. and Johansson, M. Scribble controls NGF-mediated neurite outgrowth in PC12 cells. 2013 European Journal of Cell Biology, 92 213-221

Melik, W., Ellencrona, K, Wigerius, M., Hedström, C., Elväng A., and Johansson, M. Two PDZ binding motifs within NS5 have roles in Tick-borne encephalitis virus replication, 2012, Virus research 169(1) 54-62

Wigerius M., Melik W., Elväng A. and Johansson M. Rac1 and Scribble are targets in arrest of neurite outgrowth by TBE virus NS5, Molecular and cellular neuroscience 2010 260-271

Ellencrona K., Syed A. and Johansson M. Flavivirus NS5 Associates with Host-Cell Proteins Zonula Occludens-1 and the Regulating Synaptic Membrane Exocytosis-2 Via an Internal PDZ Binding Mechanism, Biological Chemistry. 2009 390; 319-323

Werme K., Wigerius M., and Johansson M. Tick-Borne Encephalitis Virus NS5 associates with membrane protein Scribble and impairs interferon stimulated JAK-STAT signaling, Cellular microbiology 2008 10(3), 696-712

Brooks, A. J., Johansson, M., John A.,V., Xu, Y., Jans, D. A. and Vasudevan, S. G. “The importin-b binding region of dengue virus NS5 protein is a functional nuclear localisation signal (NLS) that is coupled to other NLS sequences in the interdomain region.” Journal of Biological Chemistry (2002), 277, 36399-36407

Vasudevan, S.G., Johansson, M., Brooks, A.J., Llewellyn, L.E., Jans, D.A. "Characterisation of inter- and intra- molecular interactions of the dengue virus RNA dependent RNA polymerase as potential drug targets" Il Farmaco (2001) 33-36

Johansson, M., Brooks, A.J., Jans, D.A. and Vasudevan, S.G. "A small region of the dengue virus-endcoded RNA-dependent RNA polymerase, NS5, confers interaction with both the nuclear transport receptor importin-b and the viral helicase, NS3", Journal of General Virology (2001), 82, 735-745