Targeting of TAK1 by the NF-kappa B protein Relish regulates the JNK-mediated immune response in Drosophila.
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.
Park
Jin Mo
JM
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, 92093-0636, USA.
Brady
Helen
H
Ruocco
Maria Grazia
MG
Sun
Huaiyu
H
Williams
DeeAnn
D
Lee
Susan J
SJ
Kato
Tomohisa
T
Richards
Normand
N
Chan
Kyle
K
Mercurio
Frank
F
Karin
Michael
M
Wasserman
Steven A
SA
D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000276:immunology*; D004331:Drosophila melanogaster / Q000235:genetics / Q000276:immunology; D010450:Endopeptidases / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000276:immunology; D007109:Immunity / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B; D020239:Receptor Cross-Talk / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology; D000099151:MAP Kinase Kinase Kinase 7
D029721:Drosophila Proteins; D010450:Endopeptidases; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D014157:Transcription Factors; D000099151:MAP Kinase Kinase Kinase 7; C101626:Rel protein, Drosophila