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Genes & Dev. 18 (5): 584-594

Copyright © 2004 by Cold Spring Harbor Laboratory Press.


RESEARCH PAPER

Targeting of TAK1 by the NF-{kappa}B protein Relish regulates the JNK-mediated immune response in Drosophila

Jin Mo Park1, Helen Brady3, Maria Grazia Ruocco1, Huaiyu Sun2, DeeAnn Williams2, Susan J. Lee2, Tomohisa Kato, Jr.1, Normand Richards3, Kyle Chan3, Frank Mercurio3, Michael Karin1, and Steven A. Wasserman2,4

1 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, and 2 Center for Molecular Genetics, Section of Cell and Developmental Biology, Division of Biology, University of California, San Diego, La Jolla, California 92093-0636, USA; 3 Celgene Corporation, San Diego, California 92121, USA

Abstract: The molecular circuitry underlying innate immunity is constructed of multiple, evolutionarily conserved signaling modules with distinct regulatory targets. The MAP kinases and the IKK-NF-{kappa}B molecules play important roles in the initiation of immune effector responses. We have found that the Drosophila NF-{kappa}B protein Relish plays a crucial role in limiting the duration of JNK activation and output in response to Gram-negative infections. Relish activation is linked to proteasomal degradation of TAK1, the upstream MAP kinase kinase kinase required for JNK activation. Degradation of TAK1 leads to a rapid termination of JNK signaling, resulting in a transient JNK-dependent response that precedes the sustained induction of Relish-dependent innate immune loci. Because the IKK-NF-{kappa}B module also negatively regulates JNK activation in mammals, thereby controlling inflammation-induced apoptosis, the regulatory cross-talk between the JNK and NF-{kappa}B pathways appears to be broadly conserved.

Key Words: MAPKKK • signal transduction • rel protein • proteosome • Imd

Received for publication November 6, 2003. Accepted for publication January 28, 2004.


Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1168104.

4 Corresponding author.

E-MAIL stevenw{at}ucsd.edu; FAX (858) 534-7073.

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