title: MyD88-induced downregulation of IRAK-4 and its structural requirements.
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.
authors.affiliation: Department of Metabolic Care and Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hatao
authors.forename: Maya
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Muroi
authors.forename: Michio
authors.initials: M
authors.lastname: Kaminishi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Tanamoto
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis* / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C470409:TICAM1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases