Regulation of TRAF2 signaling by self-induced degradation.
Receptors belonging to the tumor necrosis factor receptor (TNF-R) family utilize cytoplasmic adapter proteins called TNF-R-associated factors (TRAFs) as key elements in their signaling pathways. However, it is not yet clear how individual TRAFs regulate signaling by this large and growing receptor family. Signaling via the TNF-R family member CD40 has recently been shown to result in recruitment of TRAF2 to plasma membrane detergent-resistant microdomains (lipid rafts) as well as to subsequently initiate TRAF2 degradation. As TRAF2 associates with most members of the TNF-R family, we wished to determine how this degradation occurs. We show here that CD40-mediated TRAF2 degradation requires the zinc-binding RING domain of TRAF2 and is preceded by TRAF2 ubiquitination, suggesting that the TRAF2 RING may promote ubiquitination although the RING itself is not a target of ubiquitination. Several approaches show that ubiquitination and proteasomal activity are integral to TRAF2 degradation, and inhibition of this process potentiates CD40 signaling.
Brown
Kevin D
KD
Department of Microbiology and Internal Medicine, University of Iowa College of Medicine and the Veteran's Affairs Medical Center, Iowa City, Iowa 52242, USA.
Hostager
Bruce S
BS
Bishop
Gail A
GA
D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003546:Cysteine Endopeptidases; D004247:DNA / Q000378:metabolism; D007313:Insecta; D048031:JNK Mitogen-Activated Protein Kinases; D008239:Lysine / Q000737:chemistry; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D019013:CD40 Antigens; D009097:Multienzyme Complexes; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D025801:Ubiquitin; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D015032:Zinc; D008239:Lysine