Genes Dev. 1999 Oct 1;13(19):2514-26.

Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis.External

Lin, Y., Devin, A., Rodriguez, Y., Liu, Z. G.,
--- - Department of Cell and Cancer Biology, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Although the molecular mechanisms of TNF signaling have been largely elucidated, the principle that regulates the balance of life and death is still unknown. We report here that the death domain kinase RIP, a key component of the TNF signaling complex, was cleaved by Caspase-8 in TNF-induced apoptosis. The cleavage site was mapped to the aspartic acid at position 324 of RIP. We demonstrated that the cleavage of RIP resulted in the blockage of TNF-induced NF-kappaB activation. RIPc, one of the cleavage products, enhanced interaction between TRADD and FADD/MORT1 and increased cells' sensitivity to TNF. Most importantly, the Caspase-8 resistant RIP mutants protected cells against TNF-induced apopotosis. These results suggest that cleavage of RIP is an important process in TNF-induced apoptosis. Further more, RIP cleavage was also detected in other death receptor-mediated apoptosis. Therefore, our study provides a potential mechanism to convert cells from life to death in death receptor-mediated apoptosis.
PMID: 10521396External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
DD FADD Link TRADD Co-immunoprecipitation HeLa 10521396
DD FADD Link TRADD Co-immunoprecipitation HEK293 Not specified Not specified Not specified Not specified 10521396
DD RIP Link TRADD Co-immunoprecipitation HeLa 10521396
DD RIP Link TRADD Co-immunoprecipitation HEK293 Not used Not specified Not specified 10521396
(Link: click this icon to show interactions only between the two corresponding DDs)