Unraveling the repertoire of cell-death proteins

Proper regulation of cell death is crucial to organism development and to prevent cancer and diseases of the immune system. Molecular biologists in Australia have now shown that inhibitor of apoptosis (IAP) proteins not only inhibit the cell suicide process known as apoptosis but, by interacting with proteins called RIP kinases, they also help control a second cell-death mechanism: necroptosis¹. 

Without IAP proteins, mice die halfway through embryonic development. However, the functions of the three IAP proteins — cIAP1, cIAP2 and XIAP — overlap so closely that the lack of just one of them in mice affects development only slightly.

To sort out the individual roles of these proteins, David Vaux and colleagues at Australia’s Walter and Eliza Hall Institute of Medical Research and La Trobe and Melbourne universities deleted the genes coding for two of the proteins at a time. They found that a viable embryo could develop when cIAP1 alone was active, but otherwise at least two IAP proteins were necessary.

The researchers also discovered that embryonic survival of IAP mutants could be extended by deleting RIP kinases 1 and 3, which are involved in regulating necroptosis. This indicates that the RIP kinases are held in check by IAP proteins during development.