Open AccessCompetitive Control of Independent Programs of Tumor Necrosis Factor Receptor-Induced Cell Death by TRADD and RIP1
Author(s) -
Lixin Zheng,
Nicolas Bidère,
David Staudt,
Alan Cubre,
Jan M. Orenstein,
Francis KaMing Chan
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.26.9.3505-3513.2006
Subject(s) - tradd , biology , tumor necrosis factor receptor , traf2 , tumor necrosis factor alpha , tumor necrosis factor receptor 1 , programmed cell death , cancer research , receptor , microbiology and biotechnology , death domain , vascular endothelial growth inhibitor , transcription factor , apoptosis , immunology , genetics , vascular endothelial growth factor , gene , vascular endothelial growth factor a , vegf receptors
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-κB 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-κB 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-κB activation, apoptosis, and nonapoptotic death signals through separate and competing signaling pathways.