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ABSTRACT: Proteins with death effector domains (DED) are key signal transducers involved in cell death and inflammation. In this issue of Cell, Sun et al. (2008) describe TIPE2, a DED protein that negatively regulates both T cell receptor and Toll-like receptor signaling. These findings reveal a new element critical to the maintenance of homeostasis in both the adaptive and innate immune systems.
Cell 06/2008; 133(3):401-2. · 32.40 Impact Factor
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Fengyi Wan,
D Eric Anderson,
Robert A Barnitz,
Andrew Snow, Nicolas Bidere,
Lixin Zheng,
Vijay Hegde,
Lloyd T Lam,
Louis M Staudt,
David Levens,
Walter A Deutsch,
Michael J Lenardo
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ABSTRACT: NF-kappaB is a DNA-binding protein complex that transduces a variety of activating signals from the cytoplasm to specific sets of target genes. To understand the preferential recruitment of NF-kappaB to specific gene regulatory sites, we used NF-kappaB p65 in a tandem affinity purification and mass spectrometry proteomic screen. We identified ribosomal protein S3 (RPS3), a KH domain protein, as a non-Rel subunit of p65 homodimer and p65-p50 heterodimer DNA-binding complexes that synergistically enhances DNA binding. RPS3 knockdown impaired NF-kappaB-mediated transcription of selected p65 target genes but not nuclear shuttling or global protein translation. Rather, lymphocyte-activating stimuli caused nuclear translocation of RPS3, parallel to p65, to form part of NF-kappaB bound to specific regulatory sites in chromatin. Thus, RPS3 is an essential but previously unknown subunit of NF-kappaB involved in the regulation of key genes in rapid cellular activation responses. Our observations provide insight into how NF-kappaB selectively controls gene expression.
Cell 12/2007; 131(5):927-39. · 32.40 Impact Factor
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ABSTRACT: 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.
Molecular and Cellular Biology 06/2006; 26(9):3505-13. · 5.53 Impact Factor
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ABSTRACT: Previous studies have implicated the transcription factor FoxO3a in apoptosis induction. Thus, it comes as a surprise in this issue of Immunity that lymphoproliferative disease in Foxo3a-deficient mice may be due to T cell hyperactivity instead of cell death defects. Lin and colleagues provide important new evidence that disease development is associated with NF-kappaB hyperactivation in T cells.
Immunity 09/2004; 21(2):133-4. · 21.64 Impact Factor
