Mol Cell Biol. 2006 May;26(9):3505-13.

Competitive control of independent programs of tumor necrosis factor receptor-induced cell death by TRADD and RIP1.External

Zheng, L., Bidere, N., Staudt, D., Cubre, A., Orenstein, J., Chan, F. K., Lenardo, M.,
--- - Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, 9000 Rockville Pike, 10/11D09, Bethesda, MD 20892, USA. lzheng@niaid.nih.gov
Stimulation of tumor necrosis factor receptor 1 (TNFR1) can initiate several cellular responses, including apoptosis, which relies on caspases, necrotic cell death, which depends on receptor-interacting protein kinase 1 (RIP1), and NF-kappaB activation, which induces survival and inflammatory responses. The TNFR-associated death domain (TRADD) protein has been suggested to be a crucial signal adaptor that mediates all intracellular responses from TNFR1. However, cells with a genetic deficiency of TRADD are unavailable, precluding analysis with mature immune cell types. We circumvented this problem by silencing TRADD expression with small interfering RNA. We found that TRADD is required for TNFR1 to induce NF-kappaB activation and caspase-8-dependent apoptosis but is dispensable for TNFR1-initiated, RIP1-dependent necrosis. Our data also show that TRADD and RIP1 compete for recruitment to the TNFR1 signaling complex and the distinct programs of cell death. Thus, TNFR1-initiated intracellular signals diverge at a very proximal level by the independent association of two death domain-containing proteins, RIP1 and TRADD. These single transducers determine cell fate by triggering NF-kappaB activation, apoptosis, and nonapoptotic death signals through separate and competing signaling pathways.
PMID: 16611992External
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 RIP Link TNFR1 Co-immunoprecipitation Jurkat 16611992
DD TNFR1 Link TRADD Co-immunoprecipitation Jurkat 16611992
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Functional Role
Family DD1 DD2 Method Death-related Death-unrelated Reference
DD RIP Link TNFR1 Propidium iodide staining Apoptosis (DISC) NF-kB activation (DISC) 16611992
DD TNFR1 Link TRADD Propidium iodide staining Apoptosis (DISC) NF-kB activation (DISC) 16611992
(Link: click this icon to show interactions only between the two corresponding DDs)