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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Zheng, L; Bidere, N; Staudt, D; Cubre, A; Orenstein, J; Chan, FK; Lenardo, M

Published Date

  • May 2006

Published In

Volume / Issue

  • 26 / 9

Start / End Page

  • 3505 - 3513

PubMed ID

  • 16611992

Pubmed Central ID

  • 16611992

International Standard Serial Number (ISSN)

  • 0270-7306

Digital Object Identifier (DOI)

  • 10.1128/MCB.26.9.3505-3513.2006

Language

  • eng

Conference Location

  • United States