ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway.
Activation of NF-kappaB as a consequence of signaling through the Toll and IL-1 receptors is a major element of innate immune responses. We report the identification and characterization of a novel intermediate in these signaling pathways that bridges TRAF6 to MEKK-1. This adapter protein, which we have named ECSIT (evolutionarily conserved signaling intermediate in Toll pathways), is specific for the Toll/IL-1 pathways and is a regulator of MEKK-1 processing. Expression of wild-type ECSIT accelerates processing of MEKK-1, whereas a dominant-negative fragment of ECSIT blocks MEKK-1 processing and activation of NF-kappaB. These results indicate an important role for ECSIT in signaling to NF-kappaB and suggest that processing of MEKK-1 is required for its function in the Toll/IL-1 pathway.
Kopp
E
E
Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute (HHMI), Yale University School of Medicine, New Haven, Connecticut 06520 USA.
Medzhitov
R
R
Carothers
J
J
Xiao
C
C
Douglas
I
I
Janeway
C A
CA
Ghosh
S
S
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D004330:Drosophila; D029721:Drosophila Proteins; D004789:Enzyme Activation; D006801:Humans; D019476:Insect Proteins / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; C121539:ECSIT protein, Drosophila; D019476:Insect Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011506:Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D048029:TNF Receptor-Associated Factor 6; C068721:Tl protein, Drosophila; D051193:Toll-Like Receptors; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse