IKKbeta (ird5/DLAK) is the catalytic subunit of the Drosophila IkappaB kinase (IKK) complex, a cytoplasmic serine/threonine protein kinase that partners with the regulatory subunit Kenny (IKKgamma/NEMO ortholog). Activated downstream of TAK1 in the Imd pathway, it phosphorylates the NF-kappaB precursor Relish on serines 528/529, a modification needed for RNA polymerase II recruitment to antimicrobial peptide promoters, and it additionally supports Dredd-mediated endoproteolytic cleavage of Relish in a kinase-independent manner. IKKbeta is required for the antibacterial humoral immune response against Gram-negative bacteria but not for Toll-pathway activation of Dif and Dorsal. It also acts downstream of dSTING in an NF-kappaB-dependent antiviral pathway and contributes to hypoxia-induced NF-kappaB activation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002230 positive regulation of defense response to virus by host | IMP PMID:19763182 A novel system for the launch of alphavirus RNA synthesis re... | ACCEPT | Summary: Imd pathway mutants (including IKKbeta) show enhanced Sindbis virus replication, supporting a role in host antiviral defense. Reason: IKKbeta is the kinase of the Imd/STING-Relish axis, which mediates inducible antiviral responses in flies. Consistent with antiviral IMP data from other papers (PMID:30119996, PMID:19829691). Supporting Evidence: PMID:19763182 We demonstrate deficits in the immune deficiency (Imd) pathway enhance viral replication while mutations in the Toll pathway fail to affect replication. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: IKKbeta has a canonical protein kinase domain (InterPro IEA). Reason: Correct but general; the more specific protein serine/threonine kinase activity is supported experimentally (PMID:19497884), so MODIFY to it, which IKKbeta already carries (IBA, IDA). Proposed replacements: protein serine/threonine kinase activity |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IKKbeta is a Ser/Thr protein kinase that directly phosphorylates Relish on S528 and S529. Reason: Direct in vitro kinase data with recombinant DmIKKbeta and mapping of Relish phosphosites establish the core catalytic activity; the IBA is consistent with the IKK family. Supporting Evidence: PMID:19497884 we show that the IKK complex controls Relish by direct phosphorylation on serines 528 and 529 PMID:11018014 the activated DmIKK complex, as well as recombinant DmIKKbeta, can phosphorylate Relish in vitro |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:19497884 Two roles for the Drosophila IKK complex in the activation o... | ACCEPT | Summary: IKKbeta is a Ser/Thr protein kinase that directly phosphorylates Relish on S528 and S529. Reason: Direct in vitro kinase data with recombinant DmIKKbeta and mapping of Relish phosphosites establish the core catalytic activity; the IBA is consistent with the IKK family. Supporting Evidence: PMID:19497884 we show that the IKK complex controls Relish by direct phosphorylation on serines 528 and 529 PMID:11018014 the activated DmIKK complex, as well as recombinant DmIKKbeta, can phosphorylate Relish in vitro |
| GO:0005515 protein binding | IPI PMID:10636911 Lipopolysaccharide-activated kinase, an essential component ... | REMOVE | Summary: Generic protein binding (interactions with Cactus, Kenny, Relish, or in a large-scale AP-MS interactome). Reason: Protein binding is uninformative. The interactions are real (IKK complex with Kenny; kinase-substrate contact with Relish/Cactus), but they are better captured by IkappaB kinase complex membership and protein serine/threonine kinase activity, which are already annotated. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:11018014 A Drosophila IkappaB kinase complex required for Relish clea... | REMOVE | Summary: Generic protein binding (interactions with Cactus, Kenny, Relish, or in a large-scale AP-MS interactome). Reason: Protein binding is uninformative. The interactions are real (IKK complex with Kenny; kinase-substrate contact with Relish/Cactus), but they are better captured by IkappaB kinase complex membership and protein serine/threonine kinase activity, which are already annotated. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:19497884 Two roles for the Drosophila IKK complex in the activation o... | REMOVE | Summary: Generic protein binding (interactions with Cactus, Kenny, Relish, or in a large-scale AP-MS interactome). Reason: Protein binding is uninformative. The interactions are real (IKK complex with Kenny; kinase-substrate contact with Relish/Cactus), but they are better captured by IkappaB kinase complex membership and protein serine/threonine kinase activity, which are already annotated. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:38944040 Next-generation Drosophila protein interactome map and its f... | REMOVE | Summary: Generic protein binding (interactions with Cactus, Kenny, Relish, or in a large-scale AP-MS interactome). Reason: Protein binding is uninformative. The interactions are real (IKK complex with Kenny; kinase-substrate contact with Relish/Cactus), but they are better captured by IkappaB kinase complex membership and protein serine/threonine kinase activity, which are already annotated. Removal does not dispute the interactions. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding inferred from the kinase domain. Reason: Required cofactor for the kinase activity; appropriate IEA. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IKKbeta is cytoplasmic, where it acts on Relish. Reason: The IKK complex acts on cytoplasmic Relish before the Rel homology domain translocates to the nucleus; IDA and IBA support cytoplasmic localization. Supporting Evidence: PMID:11018014 The N terminus of Relish then translocates to the nucleus and activates the transcription of antibacterial immune response genes |
| GO:0005737 cytoplasm | IDA PMID:11018014 A Drosophila IkappaB kinase complex required for Relish clea... | ACCEPT | Summary: IKKbeta is cytoplasmic, where it acts on Relish. Reason: The IKK complex acts on cytoplasmic Relish before the Rel homology domain translocates to the nucleus; IDA and IBA support cytoplasmic localization. Supporting Evidence: PMID:11018014 The N terminus of Relish then translocates to the nucleus and activates the transcription of antibacterial immune response genes |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IKKbeta is cytoplasmic, where it acts on Relish. Reason: The IKK complex acts on cytoplasmic Relish before the Rel homology domain translocates to the nucleus; IDA and IBA support cytoplasmic localization. Supporting Evidence: PMID:11018014 The N terminus of Relish then translocates to the nucleus and activates the transcription of antibacterial immune response genes |
| GO:0005829 cytosol | TAS Reactome:R-DME-209227 | ACCEPT | Summary: Reactome places the IRD5/Kenny complex in the cytosol where it phosphorylates Relish. Reason: Consistent with cytoplasmic localization and with the Imd signalling complex assembled at the inner face of the plasma membrane/cytosol. Supporting Evidence: Reactome:R-DME-209227 The Drosophila orthologue of IKKB (IRD5) phosphorylates Relish (REL). |
| GO:0005829 cytosol | TAS Reactome:R-DME-209240 | ACCEPT | Summary: Reactome places the IRD5/Kenny complex in the cytosol where it phosphorylates Relish. Reason: Consistent with cytoplasmic localization and with the Imd signalling complex assembled at the inner face of the plasma membrane/cytosol. Supporting Evidence: Reactome:R-DME-209227 The Drosophila orthologue of IKKB (IRD5) phosphorylates Relish (REL). |
| GO:0005829 cytosol | TAS Reactome:R-DME-214398 | ACCEPT | Summary: Reactome places the IRD5/Kenny complex in the cytosol where it phosphorylates Relish. Reason: Consistent with cytoplasmic localization and with the Imd signalling complex assembled at the inner face of the plasma membrane/cytosol. Supporting Evidence: Reactome:R-DME-209227 The Drosophila orthologue of IKKB (IRD5) phosphorylates Relish (REL). |
| GO:0006963 positive regulation of antibacterial peptide biosynthetic process | IDA PMID:10636911 Lipopolysaccharide-activated kinase, an essential component ... | ACCEPT | Summary: IKKbeta/ird5 is required for induction of antibacterial peptide genes. Reason: Loss-of-function and dominant-negative data show IKKbeta is required for antibacterial peptide gene induction via Relish; this is a direct downstream consequence of its kinase activity on Relish. Supporting Evidence: PMID:11156609 Mutations in ird5 prevent induction of six antibacterial peptide genes in response to infection but do not affect the induction of an antifungal peptide gene. PMID:10636911 These results establish that DLAK is a novel LPS-activated kinase, which is an essential signaling component for the induction of antimicrobial peptide genes following LPS treatment in Drosophila cells. PMID:9510254 We identified new genes that are required for normal induction of transcription of an antibacterial peptide during the immune response. |
| GO:0006963 positive regulation of antibacterial peptide biosynthetic process | IMP PMID:9510254 Regulated nuclear import of Rel proteins in the Drosophila i... | ACCEPT | Summary: IKKbeta/ird5 is required for induction of antibacterial peptide genes. Reason: Loss-of-function and dominant-negative data show IKKbeta is required for antibacterial peptide gene induction via Relish; this is a direct downstream consequence of its kinase activity on Relish. Supporting Evidence: PMID:11156609 Mutations in ird5 prevent induction of six antibacterial peptide genes in response to infection but do not affect the induction of an antifungal peptide gene. PMID:10636911 These results establish that DLAK is a novel LPS-activated kinase, which is an essential signaling component for the induction of antimicrobial peptide genes following LPS treatment in Drosophila cells. PMID:9510254 We identified new genes that are required for normal induction of transcription of an antibacterial peptide during the immune response. |
| GO:0008384 IkappaB kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IkappaB kinase activity; in flies the IKK complex phosphorylates the IkappaB-like NF-kappaB precursor Relish. Reason: IKKbeta is the catalytic subunit of the fly IKK complex; the IBA (contributes_to, with Kenny) and IEA are consistent with phylogeny and with direct phosphorylation of Relish, a compound p105-like protein with a C-terminal IkappaB-like domain. Supporting Evidence: PMID:19497884 Relish is a bipartite NF-kappaB precursor protein, with an N-terminal Rel homology domain and a C-terminal IkappaB-like domain, similar to mammalian p100 and p105. |
| GO:0008384 IkappaB kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IkappaB kinase activity; in flies the IKK complex phosphorylates the IkappaB-like NF-kappaB precursor Relish. Reason: IKKbeta is the catalytic subunit of the fly IKK complex; the IBA (contributes_to, with Kenny) and IEA are consistent with phylogeny and with direct phosphorylation of Relish, a compound p105-like protein with a C-terminal IkappaB-like domain. Supporting Evidence: PMID:19497884 Relish is a bipartite NF-kappaB precursor protein, with an N-terminal Rel homology domain and a C-terminal IkappaB-like domain, similar to mammalian p100 and p105. |
| GO:0008385 IkappaB kinase complex | IBA GO_REF:0000033 | ACCEPT | Summary: IKKbeta is part of the Drosophila IKK complex with Kenny. Reason: Biochemically purified complex containing DmIKKbeta and DmIKKgamma (Kenny). Supporting Evidence: PMID:11018014 Here we report the identification of a Drosophila IkappaB kinase complex containing DmIKKbeta and DmIKKgamma, homologs of the human IKKbeta and IKKgamma proteins. |
| GO:0019731 antibacterial humoral response | IMP PMID:11156609 The antibacterial arm of the drosophila innate immune respon... | ACCEPT | Summary: ird5 mutants are deficient in the antibacterial humoral response. Reason: Direct genetic evidence that ird5 mutants fail to induce antibacterial peptides and are susceptible to E. coli. Supporting Evidence: PMID:11156609 Escherichia coli survive 100 times better in ird5 adults than in wild-type animals. |
| GO:0030163 protein catabolic process | IDA PMID:11018014 A Drosophila IkappaB kinase complex required for Relish clea... | MARK AS OVER ANNOTATED | Summary: Annotation based on IKK requirement for signal-dependent Relish cleavage. Reason: The IKK complex is required for endoproteolytic processing of Relish, which is executed by the caspase Dredd, and IKK contributes noncatalytically to that cleavage (PMID:19497884). Relish processing is activation by limited proteolysis rather than protein catabolism, and IKKbeta does not perform the proteolysis; protein catabolic process overstates and misdescribes IKKbeta's role. Supporting Evidence: PMID:11018014 We show that this complex is required for the signal-dependent cleavage of Relish PMID:19497884 IKK functions noncatalytically to support Dredd-mediated cleavage of Relish file:DROME/IKKbeta/IKKbeta-deep-research-falcon.md DREDD is the caspase that cleaves Relish |
| GO:0033209 tumor necrosis factor-mediated signaling pathway | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA transfer of TNF-mediated signaling pathway from mammalian IKKs. Reason: In mammals IKKs act downstream of TNF receptors, but in Drosophila the TNF ortholog Eiger signals mainly through JNK, and IKKbeta acts in the Imd (PGRP) pathway, which is only TNFR-like by analogy. The fly-specific terms (peptidoglycan recognition protein signaling pathway, cGAS/STING signaling) describe its pathway roles; the TNF-mediated pathway term is not supported for the fly protein. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN000540281 SUPPORTS SOURCE BUT NOT TARGET Vertebrate IKKalpha/IKKbeta (human O14920, O15111; mouse Chuk) act downstream of TNF receptors, but the fly ortholog acts in the TNFR-like Imd/PGRP pathway rather than in Eiger/TNF signalling. |
| GO:0042802 identical protein binding | IPI PMID:10636911 Lipopolysaccharide-activated kinase, an essential component ... | KEEP AS NON CORE | Summary: IKKbeta self-association (homotypic interaction). Reason: Self-interaction was detected (IntAct) and is consistent with IKK complex oligomerization and autophosphorylation, but it is not itself a core function. |
| GO:0042802 identical protein binding | IPI PMID:19497884 Two roles for the Drosophila IKK complex in the activation o... | KEEP AS NON CORE | Summary: IKKbeta self-association (homotypic interaction). Reason: Self-interaction was detected (IntAct) and is consistent with IKK complex oligomerization and autophosphorylation, but it is not itself a core function. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: IKKbeta promotes NF-kappaB (Relish) activation. Reason: IKKbeta is the kinase that activates Relish in the Imd pathway; ird5 mutant flies fail to induce NF-kappaB targets after infection or hypoxia. Supporting Evidence: PMID:24993778 Here we show that hypoxia activates the IKK-NF-ΞΊB [IΞΊB (inhibitor of nuclear factor ΞΊB)-NF-ΞΊB] pathway and the immune response in Drosophila melanogaster. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IMP PMID:24993778 Hypoxia activates IKK-NF-ΞΊB and the immune response in Droso... | ACCEPT | Summary: IKKbeta promotes NF-kappaB (Relish) activation. Reason: IKKbeta is the kinase that activates Relish in the Imd pathway; ird5 mutant flies fail to induce NF-kappaB targets after infection or hypoxia. Supporting Evidence: PMID:24993778 Here we show that hypoxia activates the IKK-NF-ΞΊB [IΞΊB (inhibitor of nuclear factor ΞΊB)-NF-ΞΊB] pathway and the immune response in Drosophila melanogaster. |
| GO:0045088 regulation of innate immune response | IMP PMID:25510503 HIF-1Ξ± restricts NF-ΞΊB-dependent gene expression to control ... | ACCEPT | Summary: IKK is required for the enhanced NF-kappaB response seen after HIF-1alpha depletion. Reason: Consistent with IKKbeta as a positive component of the Imd/NF-kappaB innate immune pathway. Supporting Evidence: PMID:25510503 HIF-1Ξ± depletion enhances the NF-ΞΊB response, and this required not only the TAK-IKK complex, but also CDK6. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for positive regulation of RNA Pol II transcription. Reason: IKKbeta phosphorylation of Relish is required for recruitment of RNA polymerase II to antimicrobial peptide genes, so the effect on transcription is real but indirect, mediated by the transcription factor Relish. Supporting Evidence: PMID:19497884 Instead they are critical for recruitment of RNA polymerase II and antimicrobial peptide gene induction |
| GO:0051607 defense response to virus | IMP PMID:19829691 The Imd pathway is involved in antiviral immune responses in... | ACCEPT | Summary: IKKbeta is required for defense against picorna-like viruses and CrPV. Reason: Direct genetic evidence that dIKKbeta mutants fail to control DCV/CrV infection and Imd pathway mutants are sensitive to CrPV. Supporting Evidence: PMID:30119996 two components of the IMD pathway, the kinase dIKKΞ² and the transcription factor Relish, were required to control infection by two picorna-like viruses PMID:19829691 Loss-of-function mutations in several Imd pathway genes displayed increased sensitivity to CrPV infection and higher CrPV loads. |
| GO:0051607 defense response to virus | IMP PMID:30119996 The Kinase IKKΞ² Regulates a STING- and NF-ΞΊB-Dependent Antiv... | ACCEPT | Summary: IKKbeta is required for defense against picorna-like viruses and CrPV. Reason: Direct genetic evidence that dIKKbeta mutants fail to control DCV/CrV infection and Imd pathway mutants are sensitive to CrPV. Supporting Evidence: PMID:30119996 two components of the IMD pathway, the kinase dIKKΞ² and the transcription factor Relish, were required to control infection by two picorna-like viruses PMID:19829691 Loss-of-function mutations in several Imd pathway genes displayed increased sensitivity to CrPV infection and higher CrPV loads. |
| GO:0061057 peptidoglycan recognition protein signaling pathway | IMP PMID:14519762 Immune activation of NF-kappaB and JNK requires Drosophila T... | ACCEPT | Summary: IKKbeta is a core kinase of the PGRP (Imd) signaling pathway, acting downstream of TAK1 and upstream of Relish. Reason: This is the defining pathway role of IKKbeta in flies. Supporting Evidence: PMID:14519762 Drosophila TAK1 functions as both the Drosophila IkappaB kinase-activating kinase and the JNK kinase-activating kinase PMID:19497884 Signal-dependent activation of Relish, including cleavage, requires both the Drosophila IkappaB kinase (IKK) and death-related ced-3/Nedd2-like protein (DREDD) |
| GO:0061057 peptidoglycan recognition protein signaling pathway | IMP PMID:19497884 Two roles for the Drosophila IKK complex in the activation o... | ACCEPT | Summary: IKKbeta is a core kinase of the PGRP (Imd) signaling pathway, acting downstream of TAK1 and upstream of Relish. Reason: This is the defining pathway role of IKKbeta in flies. Supporting Evidence: PMID:14519762 Drosophila TAK1 functions as both the Drosophila IkappaB kinase-activating kinase and the JNK kinase-activating kinase PMID:19497884 Signal-dependent activation of Relish, including cleavage, requires both the Drosophila IkappaB kinase (IKK) and death-related ced-3/Nedd2-like protein (DREDD) |
| GO:0071456 cellular response to hypoxia | IMP PMID:24993778 Hypoxia activates IKK-NF-ΞΊB and the immune response in Droso... | KEEP AS NON CORE | Summary: Hypoxia activates IKK-NF-kappaB signalling, and NF-kappaB activation is required for survival in hypoxia. Reason: Supported by mutant analysis but a context-specific, secondary role of the IKK-Relish axis. Supporting Evidence: PMID:24993778 We show that NF-ΞΊB activation is required for organism survival in hypoxia. |
| GO:0140896 cGAS/STING signaling pathway | IMP PMID:30119996 The Kinase IKKΞ² Regulates a STING- and NF-ΞΊB-Dependent Antiv... | ACCEPT | Summary: dIKKbeta acts downstream of dSTING in an NF-kappaB-dependent antiviral pathway. Reason: Direct genetic evidence places dIKKbeta downstream of dSTING, transmitting the STING signal to Relish; IKKbeta is the kinase step of the fly cGAS-like/STING pathway. Supporting Evidence: PMID:30119996 dSTING participated in the control of infection by picorna-like viruses, acting upstream of dIKKΞ² to regulate expression of Nazo, an antiviral factor. |
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Download this section (compressed HTML)I-kappaB kinase &bgr; (IKK&bgr;) encodes a a component of the I&kgr;B Kinase (IKK) complex together with the product of key. IKK complex participates in the activation of the transcription factor encoded by Rel in the immune deficiency pathway. This pathway regulates the antibacterial response and other less characterized cellular processes.
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