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A more recent version of this article appeared on May 3, 2002
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Papers In Press, published online ahead of print March 5, 2002
J. Biol. Chem, 10.1074/jbc.M201000200
Submitted on January 30, 2002
Revised on February 27, 2002
Accepted on March 5, 2002

Identification of essential regions in the cytoplasmic tail of IL-1 receptor accessory protein critical for IL-1 signaling

Jürgen Radons, Stefan Gabler, Holger Wesche, Christian Korherr, Robert Hofmeister, and Werner Falk

Klinik und Poliklinik für Innere Medizin I, Universität Regensburg, Regensburg 93042

Corresponding Author: juergen.radons{at}klinik.uni-regensburg.de

Interleukin-1 (IL-1) plays an important role in inflammation and regulation of immune responses. The activated IL-1 receptor complex which consists of the IL-1 receptor type I (IL-1RI) and the IL-1 receptor accessory protein (IL-1RAcP) generates multiple cellular responses including NF-kB activation, IL-2 secretion and IL-2 promoter activation. Reconstitution experiments in EL4D6/76 cells lacking IL-1RAcP expression and IL-1 responsiveness were used to analyze structure-function relationships of the IL-1RAcP cytoplasmic tail. Mutating a potential tyrosine kinase phosphorylation motif and various conserved aa residues had no effect on IL-1 responsiveness. Truncation analyses revealed that box 3 of the TIR domain was required for NF-kB activation, IL-2 production and JNK activation whereas IL-2 promoter activation was only partially inhibited. Surprisingly, deletion of aa 527 – 534 resulted in almost complete loss of all IL-1 responsiveness. Replacement of these aa with alanyl residues did not reconstitute NF-kB activation, IL-2 production or JNK activation but partly restored IL-2 promoter activation. Immunoprecipitation data revealed a strong correlation between MyD88 binding with NF-kB activation and IL-2 production but not with IL-2 promoter activation. Taken together, our data indicate that box 3 of IL-1RAcP is critical for IL-1-dependent NF-kB activation and stabilization of IL–2 mRNA via JNK whereas aa 527 – 534 largely contribute to IL-2 promoter activation.


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