MyD88-induced downregulation of IRAK-4 and its structural requirements |
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Authors: | Hatao Fumihiko Yamamoto Maya Muroi Masashi Kaminishi Michio Tanamoto Ken-ichi |
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Affiliation: | Department of Metabolic Care and Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. |
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Abstract: | IRAK-4 plays an essential role in Toll-like receptor (TLR)/IL-1 receptor signaling. However, its signaling and regulation mechanisms have remained elusive. We have reported previously that stimulation of TLR2, TLR4 or TLR9, but not TLR3, leads to downregulation of IRAK-4 protein. Here, we show that expression of MyD88 leads to downregulation of endogenous as well as exogenously expressed IRAK-4 protein in HEK293 cells. Expression of TRIF did not cause IRAK-4 downregulation although it induced NF-kappaB activation. Expression of either a deletion mutant of MyD88 lacking its death domain or MyD88s, neither of which induced NF-kappaB activation, did not lead to IRAK-4 downregulation. MyD88-induced downregulation was observed in an IRAK-4 mutant lacking the kinase domain, but not in another mutant lacking the death domain. These results demonstrate that downregulation of IRAK-4 requires activation of the MyD88-dependent pathway and that the death domains of both MyD88 and IRAK-4 are important for this downregulation. |
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Keywords: | Toll-like receptor IL-1 receptor NF-κB |
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