CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival.
CD30 is a cell-surface receptor that can augment lymphocyte activation and survival through its ability to induce the transcription factor NF-kappaB. CD30, however, has also been implicated in the induction of apoptotic cell death of lymphocytes. Here we show that one of the effects of CD30 signal transduction is to render cells sensitive to apoptosis induced by the type 1 tumor necrosis factor receptor (TNFR1). This sensitization is dependent on the TRAF-binding sites within the CD30 cytoplasmic domain. One of the proteins that binds to these sites is TRAF2, a signal transduction molecule that is also utilized by TNFR1 to mediate the activation of several downstream kinases and transcription factors. During CD30 signal transduction, we found that binding of TRAF2 to the cytoplasmic domain of CD30 results in the rapid depletion of TRAF2 and the associated protein TRAF1 by proteolysis. These data suggest a model in which CD30 limits its own ability to transduce cell survival signals through signal-coupled depletion of TRAF2. Depletion of intracellular TRAF2 and its coassociated proteins also increased the sensitivity of the cell to undergoing apoptosis during activation of death-inducing receptors such as TNFR1. Consistent with this hypothesis, expression of a dominant-negative form of TRAF2 was found to potentiate TNFR1-mediated death. These studies provide a potential mechanism through which CD30, as well as other TRAF-binding members of the TNFR superfamily, can negatively regulate cell survival.
Duckett
C S
CS
Howard Hughes Medical Institute, Gwen Knapp Center for Lupus and Immunology Research, and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
Thompson
C B
CB
D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis; D018106:CD28 Antigens / Q000096:biosynthesis; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D017730:Ki-1 Antigen / Q000096:biosynthesis / Q000502:physiology*; D008213:Lymphocyte Activation; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection
D015703:Antigens, CD; D018106:CD28 Antigens; D017730:Ki-1 Antigen; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D047992:TNF Receptor-Associated Factor 2