Barbara Buchen

Suche


B 9 Viral regulators of the cellular ripoptosome protein complex

Principal investigator
Christoph Becker

Mentor
Alexander Steinkasser

Viral regulators of the cellular ripoptosome protein complex

Through evolution viruses have developed many different strategies to fight defense reactions of the host. During the early stages of infection, viruses can prevent the death of infected cells and therefore gain time for replication. Later during infection they can induce cell death to facilitate the exit of viruses from infected cells and their spreading in the host organism. The differential regulation of cell death plays an important role during the viral life cycle.
Recently, a new form of cell death, called necroptosis, was discovered. Necroptosis combines the morphological features of necrosis with the molecular mechanisms of apoptosis and is regulated by a protein platform called ripoptosome. A central regulator of cell death in the ripoptosome is a protein, which is denoted cFLIP. cFLIP not only regulates survival versus apoptosis, the short isoform cFLIPshort can initiate necroptosis. Interestingly, there are certain poxviruses and herpesviruses including the Kaposi's sarcoma-associated herpesvirus (KSHV) which express a protein, called vFLIP, that shares structural similarities to cFLIPshort, suggesting that this protein might enable these viruses to regulate the ripoptosome and to reprogram cell death.
In this project it will be investigated whether vFLIP-mediated ripoptosome regulation influences viral replication and organ pathogenesis. Furthermore the role of KSHV-vFLIP on necroptosis and ripoptosome formation in different in vitro overexpression systems and on the viral life cycle in infected cells will be elucidated. Moreover the role of KSHV-vFLIP on tissue homeostasis in gut and liver will be investigated using conditional mouse model systems. Finally, the impact of the results obtained above will be validated at the clinical level using serologic analyses and expression studies in Kaposi's sarcoma, inflammatory bowel disease and colorectal cancer.

Figure: cFLIPshort binds to caspase-8 and blocks its activity. On the one hand the lack of caspase-8 activity inhibits apoptosis, on the other hand the cellular kinase RIP1 can't be cleaved anymore and forms a heterodimer with RIP3. After autophosphorylation of this heterodimer necroptosis is initiated. The structural similarities of vFLIP to cFLIPshort suggest that the virus might be able to regulate the ripoptosome and reprogram cell death.

 

Publications

Günther C., Buchen B., He G., Hornef M., Torow N., Neumann H., Wittkopf N., Martini E., Basic M., Bleich A., Neurath M. F., Becker C. (2015). Caspase-8 controls the gut response to microbial challenges by TNFα-dependent and independent pathways. Gut 64(4):601-10

Günther C., Buchen B., Neurath M. F., Becker C. (2014). Regulation and pathophysiological role of epithelial turnover in the gut. Semin Cell Dev Biol. 35:40-50

 

Presentations

October 2016 8th Annual Retreat, Erlangen School of Molecular Communication, Schloss Schney, Lichtenfels, Germany
"Expression of KSHV vFLIP in epithelial cells is sufficient to drive chronic intestinal inflammation in vivo"
Poster
     
October 2015 2nd International SFB 796 Conference: Mechanisms of microbial host cell manipulation: From plants to humans, Erlangen, Germany
A single viral caspase-8 inhibitor promotes inflammation and epithelial cell death in vivo
Poster
     
July 2015 7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany
"The influence of KSHV vFLIP on the cell death platform and the intestinal homeostasis"
Talk
     
July 2015 International Conference of Mucosal Immunology, Berlin, Germany
"A single viral caspase-8 inhibitor is able to disrupt intestinal immune homeostasis in vivo"
Poster
     
July 2014 6th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
"A single viral protein regulates the host cell death machinery in vivo
Talk
     
May 2014 Falk Symposium 192, Paris, France
A single viral protein is able to disrupt intestinal immune homeostasis in vivo”
Poster
     
May 2014 Digestive Disease Week, Chicago, USA
A single viral protein is able to disrupt intestinal immune homeostasis
Poster
     
October 2013 13. IZKF-Doktorandenworkshop, Erlangen, Germany
The consequence of vFLIP expression for intestinal homeostasis
Poster
     
July 2013 5th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
The consequence of vFlip expression for intestinal homeostasis
Talk
     

 

Awards

Best Poster Award

Second place

8th Annual Retreat, Erlangen School of Molecular Communication, Schloss Schney, Lichtenfels, Germany, October 2016
"Expression of KSHV vFLIP in epithelial cells is sufficient to drive chronic intestinal inflammation in vivo"

Best Talk Award

first place

7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany, July 2015
"The influence of KSHV vFLIP on the cell death platform and the intestinal homeostasis"