C.H.S.-Stiftung
zur Förderung biomedizinischer Forschung
Prof. Oliver T. Fackler
| 1997 | Dr.rer.nat, University of the Saarland, Dept. of Virology, Institute for Microbiology |
| 1997-2001 | Postdoc, University of California, San Francisco |
| Since 2001 | Group Leader, Dept. of Virology, University Hospital of Heidelberg |
| 2004 | Habilitation (Experimental Virology) |
| 2007 | Appointment as a Professor at the University of Heidelberg Supported by a C.H.S. Fellowship for Research Group Leaders: 2004-2007 |
Research
The Nef protein of the Human immunodeficiency Virus Type 1 (HIV-1) is a critical factor for optimal virus replication and pathogenesis in the infected host. Nef serves as protein interaction adaptor with numerous machineries of the host cell, thereby affecting multiple intracellular transport and signal transduction processes. Together, these activities are thought to optimize virus infectivity and replication and to facilitate the escape of productively infected cells from recognition by the host’s immune system. Our research generally aims at the characterization of the molecular mechanisms underlying the biologically relevant activities and protein interactions of the Nef protein. One line of experiments therefore pursues the characterization of Nef activities in HIV infection of physiologically relevant primary cell systems. Another aspect of our work is devoted to the effects of Nef on signal transduction via the T cell receptor (TCR) originating from detergent-resistant microdomains of the plasma membrane, where Nef induces an intermediate state of activation that facilitates HIV replication. Our recent findings indicate that Nef impacts on actin remodelling processes that occur in response to TCR triggering, thus enabling us to utilize Nef as a tool to study the role of the actin cytoskeleton in TCR signal transduction. Finally, we are attempting to understand how Nef affects select transport routes of cell surface receptors and how transport of Nef itself to the inner leaflet of the plasma membrane is achieved.
As our second research interest, we are studying the molecular biology of the Diaphanous Related Formin (DRF) FHOD1. The DRF protein family comprises a set of actin nucleators that remodel the actin cytoskeleton and serve as effector molecules for specific Rho GTPases. In the case of FHOD1, overexpression of an activated variant results in the formation of thick actin stress fibers and the Rac1 GTPase has been identified as specific GTPase interaction partner. The physiological role of FHOD1 and the regulation of its activity however are unclear. One aim of our studies is to unravel the molecular mechanism by which FHOD1 induces the formation of actin stress fibers. We are also addressing the relevance of the interaction of FHOD1 with the Rac1 GTPase and attempt to identify the cellular processes that are controlled by the actin remodelling capacity of endogenous FHOD1.
Selected Publications:
Original papers
Michel, N., Allespach, I., Venzke, S., Fackler, O.T. and Keppler O.T. (2005). HIV Nef induces superinfection immunity by a dual strategy to downregulate cell surface CCR5 and CD4. Curr. Biol. 15: 714-723.
Gasteier J.E., Schroeder S., Muranyi W., Madrid R., Benichou S. and Fackler O.T. (2005). FHOD1 coordinates actin filament and microtubule alignment to mediate cell elongation. Exp. Cell Res. 306: 192-202
Keppler O.T., Allespach I., Schüller L., Fenard D., Greene W.C. and Fackler O.T. (2005). Rodent Cells Support Key Functions of the Human Immunodeficiency Virus Type 1 Pathogenicity Factor Nef. J. Virol. 79: 1655-1665.
Krautkrämer E., Giese S.I., Gasteier J.E., Muranyi W. and Fackler O.T. (2004). HIV-1 Nef activates Pak via recruitment into lipid rafts. J. Virol. 78: 4085-4097.
Gasteier J.E., Madrid R., Krautkrämer E., Schröder S., Muranyi W., Benichou S. and Fackler O.T. (2003). Activation of the Rac interaction partner formin homology 2 domain containing 1 (FHOD1) induces actin stress fibers via a ROCK dependent mechanism. J. Biol. Chem. 278: 38902-38912
Fackler O.T., Wolf D., Weber H.O., Laffert B., D’Aloja, P., Schuler-Thurner, B., Geffin R., Saksela K., Geyer M., Peterlin B.M., Schuler, G. and Baur A.S. (2001). A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T-cells. Curr. Biol. 11: 1294-1299
Fackler O.T., Lu X., Frost J. A., Geyer M., Jiang B., Luo W., Abo A., Alberts A.S. and Peterlin B.M. (2000). Pak1 plays a critical role in cellular activation by Nef. Mol. Cell. Biol. 20: 2619-2627.
Fackler O.T., Luo W., Geyer M., Alberts A.S. and Peterlin B.M. (1999). Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions. Mol. Cell 3: 729-739.
Reviews
Fackler O.T. and Baur A.S. (2002). Live and let die: Functions of Nef beyond HIV replication. Immunity 16: 493-497.
Geyer M., Fackler O.T., and Peterlin B.M. (2001). Structure-Function Relationship in HIV-1 Nef. EMBO Rep. 2: 580-585.
Contact
Prof. Oliver T. Fackler
Hygiene Institut
Abt. Virologie
Im Neuenheimer Feld 324
69120 Heidelberg
Phone: ++49-(0)6221-56-1322
Fax: ++49-(0)6221-56-5003
Email: oliver.fackler@med.uni-heidelberg.de
Homepage: http://www.klinikum.uni-heidelberg.de/index.php?id=6555