A novel TNF receptor-associated factor 6 binding domain mediates NF-kappa B signaling by the common cytokine receptor beta subunit.
GM-CSF, IL-3, and IL-5 are proinflammatory cytokines that control the production and function of myeloid and lymphoid cells. Their receptors are composed of a ligand-specific alpha subunit and a shared common signal-transducing beta subunit (beta common receptor or GM-CSFR beta [beta(c)]). The pleiotropic nature of biologic outcomes mediated by beta(c) and the presence of large, uncharacterized regions of its cytoplasmic domain suggest that much remains to be learned about its downstream signaling pathways. Although some previous work has attempted to link beta(c) with NF-kappaB activation, a definitive mechanism that mediates this pathway has not been described and, to date, it has not been clear whether the receptor can directly activate NF-kappaB. We demonstrate that NF-kappaB activation by beta(c) is dependent on TNFR-associated factor 6 (TRAF6) and that association of TRAF6 with beta(c) requires a consensus-binding motif found in other molecules known to interact with TRAF6. Furthermore, point mutation of this motif abrogated the ability of beta(c) to mediate NF-kappaB activation and reduced the viability of an IL-3-dependent hematopoietic cell line. Because this receptor plays a key role in hematopoiesis and the beta(c) cytoplasmic domain identified in this work mediates hematopoietic cell viability, this new pathway is likely to contribute to immune cell biology. This work is significant because it is the first description of a TRAF6-dependent signaling pathway associated with a type I cytokine receptor. It also suggests that TRAF6, a mediator of TNFR and TLR signaling, may be a common signaling intermediate in diverse cytokine receptor systems.
Meads
Mark B
MB
Department of Experimental Therapeutics and Oncologic Sciences, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
Li
Zhi-Wei
ZW
Dalton
William S
WS
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D002999:Clone Cells; D016384:Consensus Sequence; D053648:Cytokine Receptor Common beta Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D014176:Protein Biosynthesis / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000276:immunology; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D053648:Cytokine Receptor Common beta Subunit; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D048029:TNF Receptor-Associated Factor 6