Regulated commitment of TNF receptor signaling: a molecular switch for death or activation.
Tumor necrosis factor receptor (TNFR) superfamily members can induce a context-dependent apoptosis or cell activation. However, the mechanisms by which these opposing programs are selected remain unclear. We show that in T cells, TNFR2 (TNFRSF1B) signaling is dramatically affected by the intracellular mediator RIP, a protein Ser/Thr kinase required for NF-kappaB activation by TNFR1 (TNFRSF1A). In the presence of RIP, TNFR2 triggers cell death, whereas in the absence of RIP, TNFR2 activates NF-kappaB. RIP is induced during IL2-driven T cell proliferation, and its inhibition reduces susceptibility to TNF-dependent apoptosis. Evidence that signaling outputs are shaped by intracellular constraints helps reconcile conflicting views of TNFR1 and TNFR2 as apoptotic mediators.
Pimentel-Muiños
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FX
Department of Molecular Biology, Massachusetts General Hospital, Boston 02114, USA.
Seed
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D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D020672:I-kappa B Proteins; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014764:Viral Proteins; D051020:bcl-X Protein
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015843:Serpins; D014764:Viral Proteins; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha; C074641:interleukin-1beta-converting enzyme inhibitor; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases