The role of cIAPs and their regulation of RIP Kinases in necroptosis and inflammation signalling pathways - Do cIAP knock-out mice age prematurely?
Event details
| Date | 18.12.2013 |
| Hour | 14:30 › 15:30 |
| Speaker |
John Silke, Ph.D., The Walter and Eliza Hall Institute, Parkville, Victoria, Australia Details: see website at http://www.wehi.edu.au/faculty_members/associate_professor_john_silke |
| Location | |
| Category | Conferences - Seminars |
A seminar of the Lausanne Integrative Metabolism and Nutrition Alliance (LIMNA)
Abstract:
Necroptosis is a genetically programmed cell death that is caspase independent and RIPK3 and MLKL dependent. In distinction to apoptosis, necroptotic cell death is believed to provoke an inflammatory response and loss of this cell death pathway has been shown to ameliorate some inflammatory diseases. We have shown that cIAP1 and cIAP2 double knock-out mice die at embryonic stage E10.5. This is the same developmental stage that any of the caspase-8, cFLIP or FADD knock-out mice die and it is likely that they all die from the same causes because each knock-out is protected by combined loss of the necroptosis inducing kinase RIPK3. Furthermore, this embryonic death is driven by TNFR1 signaling because combined loss of Tnfr1 also protects these mice. Unfortunately the early embryonic death of these mice makes it difficult to determine the underlying cause and in particular to distinguish whether necroptotic death causes a lethal inflammation or alternatively whether necroptosis is a epiphenomenon of an underlying inflammatory problem. We have now analysed Ripk1-/- mice; these knock-outs are one of the last major components of the TNFR1 signaling complex to be investigated in detail and the reason for their perinatal death is unknown. Using a host of knock-out mice we show that death at birth is due to a sterile but MyD88 dependent systemic inflammatory syndrome that is driven by RIPK1/RIPK3/MLKL mediated necroptotic cell death. In addition I intend to discuss the phenotype of the tissue specific cIAP knock-out animals that are viable but which develop an inflammatory syndrome that leads to their early death. This inflammatory syndrome is also highly likely to be driven by TNFR1/RIPK1/RIPK3 induced necroptotic cell death. Together these studies demonstrate the critical role that IAPs play to regulate the RIP kinases to prevent necroptosis and inflammation and suggest that targeting the necroptosis cell death pathway could be useful therapeutically. Time permitting I'd like to mention some progress we've made in this area.
Abstract:
Necroptosis is a genetically programmed cell death that is caspase independent and RIPK3 and MLKL dependent. In distinction to apoptosis, necroptotic cell death is believed to provoke an inflammatory response and loss of this cell death pathway has been shown to ameliorate some inflammatory diseases. We have shown that cIAP1 and cIAP2 double knock-out mice die at embryonic stage E10.5. This is the same developmental stage that any of the caspase-8, cFLIP or FADD knock-out mice die and it is likely that they all die from the same causes because each knock-out is protected by combined loss of the necroptosis inducing kinase RIPK3. Furthermore, this embryonic death is driven by TNFR1 signaling because combined loss of Tnfr1 also protects these mice. Unfortunately the early embryonic death of these mice makes it difficult to determine the underlying cause and in particular to distinguish whether necroptotic death causes a lethal inflammation or alternatively whether necroptosis is a epiphenomenon of an underlying inflammatory problem. We have now analysed Ripk1-/- mice; these knock-outs are one of the last major components of the TNFR1 signaling complex to be investigated in detail and the reason for their perinatal death is unknown. Using a host of knock-out mice we show that death at birth is due to a sterile but MyD88 dependent systemic inflammatory syndrome that is driven by RIPK1/RIPK3/MLKL mediated necroptotic cell death. In addition I intend to discuss the phenotype of the tissue specific cIAP knock-out animals that are viable but which develop an inflammatory syndrome that leads to their early death. This inflammatory syndrome is also highly likely to be driven by TNFR1/RIPK1/RIPK3 induced necroptotic cell death. Together these studies demonstrate the critical role that IAPs play to regulate the RIP kinases to prevent necroptosis and inflammation and suggest that targeting the necroptosis cell death pathway could be useful therapeutically. Time permitting I'd like to mention some progress we've made in this area.
Links
Practical information
- Informed public
- Free
Organizer
- Kristina Schoonjans and Johan Auwerx (for the LIMNA Alliance)
Contact
- Johan Auwerx
(*) IMPORTANT NOTICE : All external participants have to pass through SV Reception/Welcome Desk to be able to access to AI 1153. Contact person to call at arrival at SV Reception Desk: Johan Auwerx 30951 / Administrative Assistant: 39522.