A novel TNF receptor-associated factor 6 binding domain mediates NF-κB signaling by the common cytokine receptor β subunit
MB Meads, ZW Li, WS Dalton - The Journal of Immunology, 2010 - journals.aai.org
MB Meads, ZW Li, WS Dalton
The Journal of Immunology, 2010•journals.aai.orgAbstract 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 α subunit and a shared common signal-transducing β subunit (β common receptor
or GM-CSFR β [β c]). The pleiotropic nature of biologic outcomes mediated by β 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 …
and function of myeloid and lymphoid cells. Their receptors are composed of a ligand-
specific α subunit and a shared common signal-transducing β subunit (β common receptor
or GM-CSFR β [β c]). The pleiotropic nature of biologic outcomes mediated by β 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 …
Abstract
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 α subunit and a shared common signal-transducing β subunit (β common receptor or GM-CSFR β [β c]). The pleiotropic nature of biologic outcomes mediated by β 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 β c with NF-κB 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-κB. We demonstrate that NF-κB activation by β c is dependent on TNFR-associated factor 6 (TRAF6) and that association of TRAF6 with β 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 β c to mediate NF-κB activation and reduced the viability of an IL-3–dependent hematopoietic cell line. Because this receptor plays a key role in hematopoiesis and the β 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.
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