Interleukin-1 receptor type 1 is a substrate for gamma-secretase-dependent regulated intramembrane proteolysis.
Biochemical and genetic studies have revealed that the presenilins interact with several proteins and are involved in the regulated intramembrane proteolysis of numerous type 1 membrane proteins, thereby linking presenilins to a range of cellular processes. In this study, we report the characterization of a highly conserved tumor necrosis factor ... receptor-associated factor-6 (TRAF6) consensus-binding site within the hydrophilic loop domain of presenilin-1 (PS-1). In coimmunoprecipitation studies we indicate that presenilin-1 interacts with TRAF6 and interleukin-1 receptor-associated kinase 2. Substitution of presenilin-1 residues Pro-374 and Glu-376 by site-directed mutagenesis greatly reduces the ability of PS1 to associate with TRAF6. By studying these interactions, we also demonstrate that the interleukin-1 receptor type 1 (IL-1R1) undergoes intramembrane proteolytic processing, mediated by presenilin-dependent gamma-secretase activity. A metalloprotease-dependent proteolytic event liberates soluble IL-1R1 ectodomain and produces an approximately 32-kDa C-terminal domain. This IL-1R1 C-terminal domain is a substrate for subsequent gamma-secretase cleavage, which generates an approximately 26-kDa intracellular domain. Specific pharmacological gamma-secretase inhibitors, expression of dominant negative presenilin-1, or presenilin deficiency independently inhibit generation of the IL-1R1 intracellular domain. Attenuation of gamma-secretase activity also impairs responsiveness to IL-1beta-stimulated activation of the MAPKs and cytokine secretion. Thus, TRAF6 and interleukin receptor-associated kinase 2 are novel binding partners for PS1, and IL-1R1 is a new substrate for presenilin-dependent gamma-secretase cleavage. These findings also suggest that regulated intramembrane proteolysis may be a control mechanism for IL-1R1-mediated signaling.
Mesh Terms:
Amyloid Precursor Protein Secretases, Animals, Cell Line, Cytokines, Humans, Interleukin-1 Receptor-Associated Kinases, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase Kinases, Presenilin-1, Protease Inhibitors, Protein Structure, Secondary, Protein Structure, Tertiary, Rats, Receptors, Interleukin-1 Type I, TNF Receptor-Associated Factor 6
Amyloid Precursor Protein Secretases, Animals, Cell Line, Cytokines, Humans, Interleukin-1 Receptor-Associated Kinases, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase Kinases, Presenilin-1, Protease Inhibitors, Protein Structure, Secondary, Protein Structure, Tertiary, Rats, Receptors, Interleukin-1 Type I, TNF Receptor-Associated Factor 6
J. Biol. Chem.
Date: Jan. 16, 2009
PubMed ID: 18996842
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