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Mx Proteins: Large GTPases Involved in Host Defense against RNA viruses

Investigators:

Alex von der Malsburg

Simone Gruber

Otto Haller

Georg Kochs

In collaboration with:

• Dr. Dganit Danino, Technion, Haifa, Israel: Cryoelectronmicroscopic analysis of Mx oligomers and Mx membrane interactions.
• Dr. Oliver Daumke, MDC-Berlin: Structural analysis of Mx proteins
• Prof. M. Schwemmle, Department of Virology, Freiburg: Identification of Mx-associated cellular factors.

Abstract

MxA GTPase interferes with intracellular transport of essential viral components. Membrane-associated MxA blocks the transport of LaCrosse virus nucleocapsid protein to the Golgi compartment by sequestering the viral protein into large perinuclear aggregates. (A) MxA (green) forms small dots in uninfected cells. (B) After LaCrosse virus infection MxA (green) redistributes together with the viral nucleoprotein into perinuclear complexes. The cytoskelleton is stained in red for microtubuli and the DNA is stained in blue.

Mx proteins are key components of the interferon-induced antiviral state against RNA viruses. Mx genes are induced exclusively by type I IFNs (IFN-α/β) or type III IFNs (IFN-λ) and are used to monitor biologically active IFN generated during viral infections or IFN therapies. Mx proteins are related to dynamin and other large GTPases known to be involved in intracellular transport processes. Mx GTPases have two functional domains, an N-terminal GTP-binding domain and a C-terminal effector region involved in self-assembly, and viral target recognition. As described for dynamin-like GTPases, the cytoplasmic human MxA is associated to lipid membranes in vitro and to intracellular membranes in transfected or interferon-treated cells. In contrast, the murine Mx1 is located in the nucleus. Mx proteins are potent inhibitors of influenza A virus replication when present in virus-infected cells. Likewise, Mx1-positive mice are efficiently protected against highly pathogenic influenza A viruses in contrast to mice lacking a functional Mx1 protein. Mx proteins interfere with the intracellular transport of viral components. For example, the cytoplasmic MxA protein interacts with the ribonucleoprotein complex of the influenza-like Thogoto virus.

This interaction leads to a block of transport of nucleocapsids into the nucleus, where viral transcription and replication takes place. In the case of bunyaviruses, like La Crosse virus, that have a cytoplasmic replication phase, association of MxA to the viral nucleocapsid protein leads to the sequestration of the viral protein into highly ordered perinuclear complexes and, as a consequence, to the inhibition of viral replication. The aim of the project is to investigate the molecular basis of the Mx-mediated antiviral effect. We want to characterize the physical interaction of Mx proteins with cellular and viral target structures as well as the critical regions involved in this association. We further plan to determine the three dimensional structure of Mx proteins.

Selected References

• Haller, O., Stertz, S., Kochs, G.
  The Mx GTPase family of interferon-induced antiviral protein
  Microbes and Infection 9: 1636-1643 (2007)
• Kochs, G., Reichelt, M., Danino, D., Hinshaw, J.E., Haller, O.
  Assay and functional analysis of dynamin-like Mx proteins.
  Methods in Enzymology: 404, 632-643 (2005)
• Jorns, C., Holzinger D., Thimme., Spangenberg, H.Ch., Weidmann, M., Rasenack, J., Blum, H.E., Haller, O., Kochs, G.
  Rapid and simple detection of IFN-neutralizing antibodies in chronic hepatitis C non-responsive to IFN-alpha.
  J Med Virol 78: 74-82 (2006)
• Stertz, S., Reichelt, M., Krijnse-Locker, J., Mackenzie, J., Simpson, J.C., Haller, O., Kochs, G.
  Interferon-induced, antiviral human MxA Protein localizes to a distinct subcompartment of the smooth endoplasmic reticulum.
  J Interferon and Cytokine Res. 26: 650-660 (2006)
• Holzinger, D., Jorns, C., Stertz, S., Boisson-Dupuis, S., Thimme, R., Weidmann, M., Casanova, J.-L., Haller, O., Kochs, G.
  Induction of MxA gene expression by influenza A virus requires type I or type III interferon signaling.
  J Virol 81: 7776-7785 (2007)
• Grimm, D., Staeheli, P., Hufbauer, M., Koerner, I., Martínez-Sobrido, L., Solórzano, A., García-Sastre, A., Haller, O., Kochs, G.
  Replication fitness determines high virulence of influenza A virus in mice carrying functional Mx1 resistance gene.
  Proc Natl Acad Sci Proc Natl Acad Sci 104:6806-6811 (2007)
• Tumpey, T.M., Szretter, K.J., Van Hoeven, N., Katz, J.M, Kochs, G., Haller, O., García-Sastre, A., Staeheli, P.
  The Mx1 gene protects mice against the pandemic 1918 and highly lethal human H5N1 influenza viruses.
  J Virol 81: 10818-10821 (2007)
• Dittmann, J., Stertz, S., Grimm, D., Steel, J., García-Sastre, A., Haller, O., and Kochs, G.
  Influenza A virus strains differ in sensitivity to the antiviral action of the Mx-GTPase.
  J. Virol. 82: 3624-3631 (2008).

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