A Drosophila IkappaB kinase complex required for Relish cleavage and antibacterial immunity.

Here we report the identification of a Drosophila IkappaB kinase complex containing DmIKKbeta and DmIKKgamma, homologs of the human IKKbeta and IKKgamma proteins. We show that this complex is required for the signal-dependent cleavage of Relish, a member of the Rel family of transcriptional activator proteins, and for the activation of antibacterial immune response genes. In addition, we find that the activated DmIKK complex, as well as recombinant DmIKKbeta, can phosphorylate Relish in vitro. Thus, we propose that the Drosophila IkappaB kinase complex functions, at least in part, by inducing the proteolytic cleavage of Relish. The N terminus of Relish then translocates to the nucleus and activates the transcription of antibacterial immune response genes. Remarkably, this Drosophila IkappaB kinase complex is not required for the activation of the Rel proteins Dif and Dorsal through the Toll signaling pathway, which is essential for antifungal immunity and dorsoventral patterning during early development. Thus, a yet to be identified IkappaB kinase complex must be required for Rel protein activation via the Toll signaling pathway.

[1]  Istvan Ando,et al.  Activation of the Drosophila NF‐κB factor Relish by rapid endoproteolytic cleavage , 2000, EMBO reports.

[2]  R. Zhou,et al.  Role of Drosophila IKKγ in a Toll-independent antibacterial immune response , 2000, Nature Immunology.

[3]  R. Medzhitov,et al.  Fly immunity: great expectations , 2000, Genome Biology.

[4]  J. C. Clemens,et al.  Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Hoffmann,et al.  The Rel protein DIF mediates the antifungal but not the antibacterial host defense in Drosophila. , 2000, Immunity.

[6]  M. Karin,et al.  NAK is an IκB kinase-activating kinase , 2000, Nature.

[7]  S. Hammond,et al.  An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells , 2000, Nature.

[8]  T. Maniatis,et al.  IKKε Is Part of a Novel PMA-Inducible IκB Kinase Complex , 2000 .

[9]  Sung-jun Han,et al.  Lipopolysaccharide-activated Kinase, an Essential Component for the Induction of the Antimicrobial Peptide Genes inDrosophila melanogaster Cells* , 2000, The Journal of Biological Chemistry.

[10]  D. Baltimore,et al.  NF‐κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK‐related kinase , 1999, The EMBO journal.

[11]  I. Andó,et al.  Relish, a central factor in the control of humoral but not cellular immunity in Drosophila. , 1999, Molecular cell.

[12]  M. Ashburner,et al.  Constitutive activation of toll-mediated antifungal defense in serpin-deficient Drosophila. , 1999, Science.

[13]  C. Scheidereit,et al.  NF‐κB p105 is a target of IκB kinases and controls signal induction of Bcl‐3–p50 complexes , 1999 .

[14]  A. Fire,et al.  RNA-triggered gene silencing. , 1999, Trends in genetics : TIG.

[15]  S. Akira,et al.  IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases. , 1999, International immunology.

[16]  Han Zs,et al.  Interaction and Specificity of Rel-related Proteins in Regulating Drosophila Immunity Gene Expression , 1999 .

[17]  Y. Ip,et al.  Interaction and Specificity of Rel-related Proteins in Regulating Drosophila Immunity Gene Expression* , 1999, The Journal of Biological Chemistry.

[18]  R. Steward,et al.  A mosaic analysis in Drosophila fat body cells of the control of antimicrobial peptide genes by the Rel proteins Dorsal and DIF , 1999, The EMBO journal.

[19]  F C Kafatos,et al.  Phylogenetic perspectives in innate immunity. , 1999, Science.

[20]  Y. Ip,et al.  Toll receptor-mediated Drosophila immune response requires Dif, an NF-κB factor , 1999 .

[21]  L Misquitta,et al.  Targeted disruption of gene function in Drosophila by RNA interference (RNA-i): a role for nautilus in embryonic somatic muscle formation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Zhijian J. Chen,et al.  Signal-induced ubiquitination of IκBα by the F-box protein Slimb/β-TrCP , 1999 .

[23]  M. Mann,et al.  IκB Kinase (IKK)-Associated Protein 1, a Common Component of the Heterogeneous IKK Complex , 1999, Molecular and Cellular Biology.

[24]  P. Sharp,et al.  RNAi and double-strand RNA. , 1999, Genes & development.

[25]  R. Carthew,et al.  Use of dsRNA-Mediated Genetic Interference to Demonstrate that frizzled and frizzled 2 Act in the Wingless Pathway , 1998, Cell.

[26]  E. Zandi,et al.  IKK-γ is an essential regulatory subunit of the IκB kinase complex , 1998, Nature.

[27]  A. Fire,et al.  Double-stranded RNA as a mediator in sequence-specific genetic silencing and co-suppression. , 1998, Trends in genetics : TIG.

[28]  G. Courtois,et al.  Complementation Cloning of NEMO, a Component of the IκB Kinase Complex Essential for NF-κB Activation , 1998, Cell.

[29]  T. Maniatis,et al.  Arginine/serine-rich domains of SR proteins can function as activators of pre-mRNA splicing. , 1998, Molecular cell.

[30]  K. Anderson,et al.  Regulated nuclear import of Rel proteins in the Drosophila immune response , 1998, Nature.

[31]  Jian Kang,et al.  Interaction of an Adenovirus E3 14.7-Kilodalton Protein with a Novel Tumor Necrosis Factor Alpha-Inducible Cellular Protein Containing Leucine Zipper Domains , 1998, Molecular and Cellular Biology.

[32]  S. Ghosh,et al.  Signal transduction through NF-κB , 1998 .

[33]  M J May,et al.  NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. , 1998, Annual review of immunology.

[34]  B. Lemaître,et al.  Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Matthias Mann,et al.  IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation , 1997 .

[36]  Antony Rodriguez,et al.  The 18‐wheeler mutation reveals complex antibacterial gene regulation in Drosophila host defense , 1997, The EMBO journal.

[37]  C. Janeway,et al.  Treatment of l(2)mbn Drosophila tumorous blood cells with the steroid hormone ecdysone amplifies the inducibility of antimicrobial peptide gene expression. , 1997, Insect biochemistry and molecular biology.

[38]  David M. Rothwarf,et al.  A cytokine-responsive IκB kinase that activates the transcription factor NF-κB , 1997, Nature.

[39]  D. Goeddel,et al.  Identification and Characterization of an IκB Kinase , 1997, Cell.

[40]  T. Maniatis,et al.  Activation of the IκBα Kinase Complex by MEKK1, a Kinase of the JNK Pathway , 1997, Cell.

[41]  E. Craig,et al.  Genomic libraries and a host strain designed for highly efficient two-hybrid selection in yeast. , 1996, Genetics.

[42]  D. Hultmark,et al.  Origins of immunity: Relish, a compound Rel-like gene in the antibacterial defense of Drosophila. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  K. Lewis,et al.  A P1-based physical map of the Drosophila euchromatic genome. , 1996, Genome research.

[44]  T. Maniatis,et al.  Site-Specific Phosphorylation of IκBα by a Novel Ubiquitination-Dependent Protein Kinase Activity , 1996, Cell.

[45]  K. Anderson,et al.  A conserved signaling pathway: the Drosophila toll-dorsal pathway. , 1996, Annual review of cell and developmental biology.

[46]  M. Levine,et al.  The eve stripe 2 enhancer employs multiple modes of transcriptional synergy. , 1996, Development.

[47]  M. Meister,et al.  A recessive mutation, immune deficiency (imd), defines two distinct control pathways in the Drosophila host defense. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[48]  A. Baldwin,et al.  Mechanistic aspects of NF-κB regulation: The emerging role of phosphorylation and proteolysis , 1995 .

[49]  B. Berger,et al.  Predicting coiled coils by use of pairwise residue correlations. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[50]  S. Wasserman,et al.  Interaction of the pelle kinase with the membrane-associated protein tube is required for transduction of the dorsoventral signal in Drosophila embryos. , 1995, Development.

[51]  C. Nüsslein-Volhard,et al.  Activation of the kinase Pelle by Tube in the dorsoventral signal transduction pathway of Drosophila embryo , 1994, Nature.

[52]  S. Elledge,et al.  The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. , 1993, Genes & development.

[53]  D. Hultmark,et al.  In vitro induction of cecropin genes--an immune response in a Drosophila blood cell line. , 1992, Biochemical and biophysical research communications.

[54]  C. Nüsslein-Volhard,et al.  Rescue of bicoid mutant Drosophila embryos by Bicoid fusion proteins containing heterologous activating sequences , 1989, Nature.