Signal Transduction Group:
Group leader: Dr.Rothenburg
Members of the group
(Dr. med.Stefan Rothenburg, Nikolaus Deigendesch, Jasmin Oehlmann)
Research Interest
Interferons are key molecules in the host cell response against viral infections. Antiviral activity is mediated by the induction and activation of cellular anti-viral proteins (Samuel, 2001). Our group focuses on two interferon-regulated proteins, the Z-DNA binding protein 1 (ZBP1/ tumor stroma and activated macrophage protein DLM-1) and the double stranded RNA (dsRNA) dependent protein kinase (PKR) and their role in innate immunity. We further study function of the viral antagonists of these cellular proteins.
ZBP1 was initially identified in the mouse as a gene that is up regulated in tumor stromal cells and interferon and LPS treated macrophages. It was hypothesized that it might play an important role in tumor formation (Fu et al., 1999). It was later shown that ZBP1 belongs to a family of proteins, including the interferon induced RNA editing enzyme ADAR1 and the poxvirus interferon-resistance protein E3L, that specifically bind to left-handed Z-DNA, an alternative DNA conformation, in a conformation-specific manner (Schwartz et al., 2001).
ZBP1 is a 47 kD protein which is composed of two N-terminal Z-DNA binding domains and a C-terminal domain of yet unknown function. We cloned human ZBP1 and showed the existence of a high number of alternatively spliced mRNAs (Rothenburg et al., 2002). Remarkably, in about half of the mRNAs the first of the two Z-DNA binding domains is spliced out.
We aim to further understand physiological function of ZBP1, its role in infection and tumorigenesis as well as its relationship to the poxvirus protein E3L, which has anti-apoptotic and oncogenic properties (Garcia et al., 2002).
A second project focuses on the double-stranded RNA (dsRNA)-dependent protein kinase (PKR). PKR is an important protein kinase mediating the anti-viral and anti-proliferative effects of interferons (Williams, 1999; Samuel, 2001). It possesses two dsRNA binding domains in the N-terminus and a kinase domain in the C-terminus. PKR can be activated directly by double-stranded RNA, which is formed during viral infection. Activation of PKR leads to the general inhibition of protein synthesis, inhibition of viral replication and apoptosis. The best-characterized function of PKR is the phosphorylation of the a subunit of eukaryotic translation initiation factor 2 (eIF2a). Other functions of PKR include activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. PKR has not been identified outside mammals and birds. Recently we discovered the PKR-related kinase PKZ from zebrafish, the kinase domain of which is closely related to that of PKR but contains two Z-DNA binding domains (ZBD) instead of the dsRNA binding domains (Rothenburg et al., 2005). PKZ binds to Z-DNA in vitro, is highly induced in vivo by poly I:C, a simulator of viral infection, and it inhibits protein synthesis in a manner comparable to PKR (Rothenburg et al., 2005). Phylogenetic analyses on the evolution of eIF2a kinases showed that fish PKZ is closely related to PKR.
Fu, Y., Comella, N., Tognazzi, K., Brown, L.F., Dvorak, H.F. & Kocher, O. (1999). Gene, 240, 157-163.
Garcia, M.A., Guerra, S., Gil, J., Jimenez, V. & Esteban, M. (2002). Oncogene, 21, 8379-8387.
Kim, Y.G., Muralinath, M., Brandt, T., Pearcy, M., Hauns, K., Lowenhaupt, K., Jacobs, B.L. & Rich, A. (2003). Proc. Natl. Acad. Sci. U. S. A., 100, 6974-6979.
Rothenburg, S., Deigendesch, N., Dittmar, K., Koch-Nolte, F., Haag, F., Lowenhaupt, K. & Rich, A. (2005). Proc. Natl. Acad. Sci. U. S. A., (in press).
Rothenburg, S., Schwartz, T., Koch-Nolte, F. & Haag, F. (2002). Nucleic Acids Res., 30, 993-1000.
Samuel, C.E. (2001). Clin. Microbiol. Rev., 14, 778-809.
Schwartz, T., Behlke, J., Lowenhaupt, K., Heinemann, U. & Rich, A. (2001). Nat. Struct. Biol., 8, 761-765.
Williams, B.R. (1999). Oncogene, 18, 6112-6120.
Cooperations:
Ky Lowenhaupt and
Alexander Rich, Massachusetts Institute of Technology, Cambridge, USA
Katharina Dittmar, Brigham Young University, Provo, USA
Honors and Awards:
to Stefan Rothenburg
2003 Hans-Dietrich Herrmann-Award for best thesis in molecular medicine at the University of Hamburg
2002 Graduate Stipend of the Novartis-Foundation for Therapeutic Research
2000 Travel Stipend of the German Society for Immunology for the meeting "XIIIth International Workshop on Alloantigenic Systems in the Rat", Göteborg, Sweden: (2000)
1999 Travel Stipend of the German Society for Immunology for the meeting "Mechanisms of Eukaryotic Transcription", Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA (1999)
1998 - 2000 Graduate Stipend of the Werner-Otto Foundation
1998 Short-time stipend from the Boehringer Ingelheim Fonds (3 months)
to Nikolaus Deigendesch
2004 - 2006 Graduate Stipend of the Werner-Otto Foundation
