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J. Biol. Chem. 284 (3): 1394-1409

© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

Interleukin-1 Receptor Type 1 Is a Substrate for {gamma}-Secretase-dependent Regulated Intramembrane Proteolysis*

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Baukje M. Elzinga1, Ciara Twomey1, James C. Powell, Frances Harte, , and Justin V. McCarthy2

Signal Transduction Laboratory, Biochemistry Department, University College Cork, Cork, Ireland

Abstract: 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 ~32-kDa C-terminal domain. This IL-1R1 C-terminal domain is a substrate for subsequent {gamma}-secretase cleavage, which generates an ~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-1β-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.

Received for publication April 23, 2008. Revision received November 5, 2008.

* This work was supported by Science Foundation Ireland Grant 02/IN1/B218 and the Irish Research Council for Science, Engineering, and Technology Grants SC/2003/544/Y and IC/2004/103. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

1 Both authors contributed equally to this work.

2 To whom correspondence should be addressed: Biochemistry Dept., Analytical and Biological Chemistry Research Facility, Cavanagh Pharmacy Bldg., University College Cork, Cork, Ireland. E-mail: jv.mccarthy{at}ucc.ie.

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