Dif (Dorsal-related immunity factor) encodes a Rel/NF-kappaB family transcription factor, a paralogue of Dorsal encoded at an adjacent locus, with an N-terminal Rel homology domain for kappaB-site DNA binding and dimerization and a C-terminal transactivation region. In unchallenged larval and adult fat body Dif is held in the cytoplasm by the IkappaB homologue Cactus. Infection by fungi or Gram-positive bacteria activates the Toll receptor through the cleaved cytokine Spaetzle; signalling via Myd88, Tube and Pelle leads to Cactus degradation, and Dif enters the nucleus, binds kappaB-like motifs and, with Mediator, activates antimicrobial peptide genes such as drosomycin, metchnikowin and defensin. Dif is the Toll-pathway transcription factor required for antifungal and anti-Gram-positive defence in adults and acts redundantly with Dorsal in larvae; it does not take part in embryonic dorsoventral patterning. It forms homodimers and heterodimers with Dorsal and Relish, the latter able to activate targets of both Toll and Imd pathways. Dif and Dorsal also sustain hemocyte number, and an alternative Dif B isoform is expressed in the larval mushroom bodies. Beyond antimicrobial peptide induction, Dif is required for the infection-induced depletion of the serpin Spn27A that allows melanization, and in wing imaginal discs Dif and Dorsal mediate the reaper-dependent elimination of Minute (RpL14 heterozygous) loser cells during cell competition.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:17785540 Functional conservation of Rel binding sites in drosophilid ... | ACCEPT | Summary: Protein-binding-microarray profiling of Dif affinity for kappaB variants. Reason: Dif is a Rel homology domain transcription factor that binds kappaB-like motifs in the promoters of immunity genes (Cecropin A1, drosomycin, metchnikowin); sequence-specific binding to RNA polymerase II regulatory regions is a core activity. Supporting Evidence: PMID:17785540 We employ our recently developed microarray-based experimental platform and principal coordinates statistical analysis to quantitatively and systematically profile DNA binding affinities of three Drosophila Rel proteins to 10,368 variants of the NFKB recognition sequences. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:7479760 Interactions of a Rel protein with its inhibitor. | ACCEPT | Summary: Rel protein DNA binding assayed in yeast (abstract describes Dorsal). Reason: Dif is a Rel homology domain transcription factor that binds kappaB-like motifs in the promoters of immunity genes (Cecropin A1, drosomycin, metchnikowin); sequence-specific binding to RNA polymerase II regulatory regions is a core activity. The abstract-only record describes Dorsal; the Dif experiment is presumably in the full text and the activity is not in doubt, so the curator is deferred to. Supporting Evidence: PMID:8242747 Evidence is presented that once in the nucleus, Dif binds to kappa B-like sequence motifs present in promoter regions of immunity genes. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:8242747 Dif, a dorsal-related gene that mediates an immune response ... | ACCEPT | Summary: Dif binds kappaB-like motifs in immunity gene promoters. Reason: Dif is a Rel homology domain transcription factor that binds kappaB-like motifs in the promoters of immunity genes (Cecropin A1, drosomycin, metchnikowin); sequence-specific binding to RNA polymerase II regulatory regions is a core activity. Supporting Evidence: PMID:8242747 Evidence is presented that once in the nucleus, Dif binds to kappa B-like sequence motifs present in promoter regions of immunity genes. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA sequence-specific DNA binding. Reason: Dif is a Rel homology domain transcription factor that binds kappaB-like motifs in the promoters of immunity genes (Cecropin A1, drosomycin, metchnikowin); sequence-specific binding to RNA polymerase II regulatory regions is a core activity. Supporting Evidence: PMID:8242747 Evidence is presented that once in the nucleus, Dif binds to kappa B-like sequence motifs present in promoter regions of immunity genes. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cis-regulatory region sequence-specific DNA binding. Reason: Dif is a Rel homology domain transcription factor that binds kappaB-like motifs in the promoters of immunity genes (Cecropin A1, drosomycin, metchnikowin); sequence-specific binding to RNA polymerase II regulatory regions is a core activity. PAINT placement at the Rel family node is appropriate for Dif. Supporting Evidence: PMID:8242747 Evidence is presented that once in the nucleus, Dif binds to kappa B-like sequence motifs present in promoter regions of immunity genes. PMID:7621828 This study establishes that Dif is a sequence-specific transcription factor and is probably a key activator of the immune response in Drosophila. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA DNA-binding transcription factor activity, RNA polymerase II-specific. Reason: Dif is an RNA polymerase II-specific, sequence-specific transcriptional activator of antimicrobial peptide genes downstream of Toll; this is its core molecular function. Supporting Evidence: PMID:7621828 This study establishes that Dif is a sequence-specific transcription factor and is probably a key activator of the immune response in Drosophila. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:7479760 Interactions of a Rel protein with its inhibitor. | ACCEPT | Summary: Rel transcription factor activity in yeast (abstract describes Dorsal). Reason: Dif is an RNA polymerase II-specific, sequence-specific transcriptional activator of antimicrobial peptide genes downstream of Toll; this is its core molecular function. Abstract-only record; deferred to the curator. Supporting Evidence: PMID:7621828 This study establishes that Dif is a sequence-specific transcription factor and is probably a key activator of the immune response in Drosophila. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:17296495 Isolation of regulators of Drosophila immune defense genes b... | ACCEPT | Summary: Dif activates the CecA1 promoter and interacts with POU-domain co-regulators. Reason: Dif is an RNA polymerase II-specific, sequence-specific transcriptional activator of antimicrobial peptide genes downstream of Toll; this is its core molecular function. Supporting Evidence: PMID:17296495 three transcription factors belonging to the POU domain class of homeodomain proteins, Pdm1, Pdm2 and Dfr/Vvl were isolated as Dif-interacting partners, and subsequently verified as regulators of CecA1 expression in Drosophila cells. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:8242747 Dif, a dorsal-related gene that mediates an immune response ... | ACCEPT | Summary: Dif binds and activates immunity-gene kappaB motifs. Reason: Dif is an RNA polymerase II-specific, sequence-specific transcriptional activator of antimicrobial peptide genes downstream of Toll; this is its core molecular function. Supporting Evidence: PMID:8242747 Evidence is presented that once in the nucleus, Dif binds to kappa B-like sequence motifs present in promoter regions of immunity genes. PMID:8242747 Although Dif maps close to dorsal, it does not appear to participate in DV patterning, but instead mediates an immune response in Drosophila larvae. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA transcription activator activity. Reason: Dif is an RNA polymerase II-specific, sequence-specific transcriptional activator of antimicrobial peptide genes downstream of Toll; this is its core molecular function. Supporting Evidence: PMID:7621828 We now present evidence that the Dif gene product trans-activates the Drosophila Cecropin A1 gene in co-transfection assays. |
| GO:0002225 positive regulation of antimicrobial peptide production | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA positive regulation of antimicrobial peptide production. Reason: Dif is required for Toll-dependent induction of drosomycin and other antimicrobial peptides in adults, and acts redundantly with Dorsal in larvae. A core process. Supporting Evidence: PMID:10197979 The results show that the presence of Dif without Dorsal is sufficient to mediate the induction of drosomycin and defensin. |
| GO:0002225 positive regulation of antimicrobial peptide production | IMP PMID:10369678 A mosaic analysis in Drosophila fat body cells of the contro... | ACCEPT | Summary: Dif or Dorsal rescues drosomycin inducibility in double-mutant fat body clones. Reason: Dif is required for Toll-dependent induction of drosomycin and other antimicrobial peptides in adults, and acts redundantly with Dorsal in larvae. A core process. Supporting Evidence: PMID:10369678 in the absence of both genes, the immune-inducibility of drosomycin is lost but can be rescued by overexpression of either dorsal or dif under the control of a heat-shock promoter. |
| GO:0002804 positive regulation of antifungal peptide production | IMP PMID:10843389 The Rel protein DIF mediates the antifungal but not the anti... | ACCEPT | Summary: Dif mediates Toll-dependent inducibility of the antifungal peptide gene Drosomycin. Reason: Dif is required for Toll-dependent induction of drosomycin and other antimicrobial peptides in adults, and acts redundantly with Dorsal in larvae. A core process. Supporting Evidence: PMID:10843389 Genetic epistasis experiments demonstrate that Dif mediates the Toll-dependent control of the inducibility of the antifungal peptide gene Drosomycin. PMID:10843389 DIF alone is required for the antifungal response in adults, but is redundant in larvae with Dorsal |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based generic DNA binding. Reason: Correct but uninformative parent of the sequence-specific terms. Supporting Evidence: PMID:8242747 Evidence is presented that once in the nucleus, Dif binds to kappa B-like sequence motifs present in promoter regions of immunity genes. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:7621828 The dorsal-related immunity factor, Dif, is a sequence-speci... | ACCEPT | Summary: Dif is a sequence-specific trans-activator of Cecropin A1. Reason: Dif is an RNA polymerase II-specific, sequence-specific transcriptional activator of antimicrobial peptide genes downstream of Toll; this is its core molecular function. Supporting Evidence: PMID:7621828 We now present evidence that the Dif gene product trans-activates the Drosophila Cecropin A1 gene in co-transfection assays. PMID:7621828 This study establishes that Dif is a sequence-specific transcription factor and is probably a key activator of the immune response in Drosophila. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based DNA-binding transcription factor activity. Reason: Correct; parent of GO:0000981. Supporting Evidence: PMID:7621828 This study establishes that Dif is a sequence-specific transcription factor and is probably a key activator of the immune response in Drosophila. |
| GO:0005515 protein binding | IPI PMID:12556495 Signal-induced transcriptional activation by Dif requires th... | MODIFY | Summary: Dif binds the Mediator subunit dTRAP80 (MED17). Reason: The interacting partner is dTRAP80, a Mediator subunit, and the binding is required for Dif-dependent activation of drosomycin. Mediator complex binding describes the activator-coactivator interface more informatively than protein binding. Proposed replacements: mediator complex binding Supporting Evidence: PMID:12556495 activation of Drosophila antimicrobial peptide drosomycin gene expression by the NF-kappa B-like transcription factor Dif during induction of the Toll signaling pathway was dependent on the dTRAP80 module. PMID:12556495 only a subset of these proteins interacted with dTRAP80 in vitro and only these dTRAP80-interacting activators were defective for activation under dTRAP80-deficient in vivo conditions. |
| GO:0005515 protein binding | IPI PMID:20679214 Heterodimers of NF-kappaB transcription factors DIF and Reli... | MODIFY | Summary: Dif heterodimerizes with Dorsal and Relish. Reason: Rel proteins are obligate dimers; Tanji et al. show that Dif forms heterodimers with Dorsal and Relish, and the Dif-Relish heterodimer activates targets of both Toll and IMD pathways. Protein heterodimerization activity is the informative term. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:20679214 Dorsal, DIF, and Relish are NF-kappaB-related transcription factors and function as obligate dimers PMID:20679214 The results show that all combinations of homo- and heterodimers are formed, but with varying degrees of efficiency. PMID:20679214 Our results demonstrate that the linked heterodimer can activate target genes of both the Toll and IMD pathways. |
| GO:0005515 protein binding | IPI PMID:20679214 Heterodimers of NF-kappaB transcription factors DIF and Reli... | MODIFY | Summary: Dif heterodimerizes with Dorsal and Relish. Reason: Rel proteins are obligate dimers; Tanji et al. show that Dif forms heterodimers with Dorsal and Relish, and the Dif-Relish heterodimer activates targets of both Toll and IMD pathways. Protein heterodimerization activity is the informative term. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:20679214 Dorsal, DIF, and Relish are NF-kappaB-related transcription factors and function as obligate dimers PMID:20679214 The results show that all combinations of homo- and heterodimers are formed, but with varying degrees of efficiency. PMID:20679214 Our results demonstrate that the linked heterodimer can activate target genes of both the Toll and IMD pathways. |
| GO:0005515 protein binding | IPI PMID:20679214 Heterodimers of NF-kappaB transcription factors DIF and Reli... | MODIFY | Summary: Dif heterodimerizes with Dorsal and Relish. Reason: Rel proteins are obligate dimers; Tanji et al. show that Dif forms heterodimers with Dorsal and Relish, and the Dif-Relish heterodimer activates targets of both Toll and IMD pathways. Protein heterodimerization activity is the informative term. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:20679214 Dorsal, DIF, and Relish are NF-kappaB-related transcription factors and function as obligate dimers PMID:20679214 The results show that all combinations of homo- and heterodimers are formed, but with varying degrees of efficiency. PMID:20679214 Our results demonstrate that the linked heterodimer can activate target genes of both the Toll and IMD pathways. |
| GO:0005515 protein binding | IPI PMID:7479760 Interactions of a Rel protein with its inhibitor. | REMOVE | Summary: Rel protein binding to Cactus (abstract describes Dorsal). Reason: Protein binding is uninformative. Binding of Dif to its IkappaB Cactus is the inhibitory retention complex, captured on Cactus (NF-kappaB binding); no specific MF term applies to the NF-kappaB side. Supporting Evidence: PMID:9510254 Cytoplasmic retention of both Dorsal and Dif depends on Cactus protein |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA nucleus (is_active_in). Reason: Dif is cytoplasmic in unchallenged larval fat body and accumulates in nuclei upon infection or injury; nuclear localization is required for its function. Supporting Evidence: PMID:8242747 Dif is normally localized in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. |
| GO:0005634 nucleus | IDA PMID:11943764 The Drosophila homolog of NTF-2, the nuclear transport facto... | ACCEPT | Summary: Nuclear accumulation of Dif observed experimentally. Reason: Dif is cytoplasmic in unchallenged larval fat body and accumulates in nuclei upon infection or injury; nuclear localization is required for its function. Supporting Evidence: PMID:11943764 the three NF-kappaB/Rel proteins Dorsal, Dif and Relish do not target to the nucleus after infection |
| GO:0005634 nucleus | IDA PMID:12556495 Signal-induced transcriptional activation by Dif requires th... | ACCEPT | Summary: Nuclear accumulation of Dif observed experimentally. Reason: Dif is cytoplasmic in unchallenged larval fat body and accumulates in nuclei upon infection or injury; nuclear localization is required for its function. Supporting Evidence: PMID:12556495 activation of Drosophila antimicrobial peptide drosomycin gene expression by the NF-kappa B-like transcription factor Dif during induction of the Toll signaling pathway was dependent on the dTRAP80 module. |
| GO:0005634 nucleus | IDA PMID:14585960 Discrete functions of TRAF1 and TRAF2 in Drosophila melanoga... | ACCEPT | Summary: Nuclear accumulation of Dif observed experimentally. Reason: Dif is cytoplasmic in unchallenged larval fat body and accumulates in nuclei upon infection or injury; nuclear localization is required for its function. Supporting Evidence: PMID:14585960 Ectopic expression of DTRAF2 induced nuclear translocation of two Drosophila NF-kappaBs, DIF and Relish, consequently activating the transcription of the antimicrobial peptide genes diptericin, diptericin-like protein, and drosomycin. |
| GO:0005634 nucleus | IDA PMID:17032737 The nucleoporin Nup214 sequesters CRM1 at the nuclear rim an... | ACCEPT | Summary: Nuclear Dif (Nup214 study; abstract describes Dorsal). Reason: Dif is cytoplasmic in unchallenged larval fat body and accumulates in nuclei upon infection or injury; nuclear localization is required for its function. The abstract-only record centres on Dorsal; UniProt also cites this paper for Dif localization, so the curator is deferred to. Supporting Evidence: PMID:8242747 Dif is normally localized in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. |
| GO:0005634 nucleus | IDA PMID:8242747 Dif, a dorsal-related gene that mediates an immune response ... | ACCEPT | Summary: Nuclear accumulation of Dif observed experimentally. Reason: Dif is cytoplasmic in unchallenged larval fat body and accumulates in nuclei upon infection or injury; nuclear localization is required for its function. Supporting Evidence: PMID:8242747 Dif is normally localized in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. |
| GO:0005634 nucleus | IDA PMID:9510254 Regulated nuclear import of Rel proteins in the Drosophila i... | ACCEPT | Summary: Nuclear accumulation of Dif observed experimentally. Reason: Dif is cytoplasmic in unchallenged larval fat body and accumulates in nuclei upon infection or injury; nuclear localization is required for its function. Supporting Evidence: PMID:9510254 In response to infection, two Rel proteins, Dif and Dorsal, translocate from the cytoplasm to the nuclei of larval fat-body cells. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA nucleus. Reason: Dif is cytoplasmic in unchallenged larval fat body and accumulates in nuclei upon infection or injury; nuclear localization is required for its function. Supporting Evidence: PMID:8242747 Dif is normally localized in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. |
| GO:0005654 nucleoplasm | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA nucleoplasm. Reason: Consistent with nuclear transcription factor function. Supporting Evidence: PMID:8242747 Dif is normally localized in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. |
| GO:0005654 nucleoplasm | TAS Reactome:R-DME-209218 | ACCEPT | Summary: Reactome: DL/DIF dimer activates transcription (nucleoplasm). Reason: Consistent with nuclear function. Supporting Evidence: PMID:8242747 Evidence is presented that once in the nucleus, Dif binds to kappa B-like sequence motifs present in promoter regions of immunity genes. |
| GO:0005654 nucleoplasm | TAS Reactome:R-DME-209295 | ACCEPT | Summary: Reactome: DL/DIF dimer translocation to nucleus. Reason: Consistent with nuclear function. Supporting Evidence: PMID:9510254 In response to infection, two Rel proteins, Dif and Dorsal, translocate from the cytoplasm to the nuclei of larval fat-body cells. |
| GO:0005737 cytoplasm | EXP PMID:8242747 Dif, a dorsal-related gene that mediates an immune response ... | ACCEPT | Summary: Cytoplasmic Dif in unchallenged fat body. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:8242747 Dif is normally localized in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. |
| GO:0005737 cytoplasm | IDA PMID:11943764 The Drosophila homolog of NTF-2, the nuclear transport facto... | ACCEPT | Summary: Dif fails to enter nuclei in ntf-2 hypomorphs. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:11943764 the three NF-kappaB/Rel proteins Dorsal, Dif and Relish do not target to the nucleus after infection |
| GO:0005737 cytoplasm | IDA PMID:17032737 The nucleoporin Nup214 sequesters CRM1 at the nuclear rim an... | ACCEPT | Summary: Cytoplasmic Dif (Nup214 study; abstract describes Dorsal). Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Deferred to the curator. Supporting Evidence: PMID:9510254 Cytoplasmic retention of both Dorsal and Dif depends on Cactus protein |
| GO:0005737 cytoplasm | IDA PMID:9510254 Regulated nuclear import of Rel proteins in the Drosophila i... | ACCEPT | Summary: Cactus-dependent cytoplasmic retention of Dif. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:9510254 Cytoplasmic retention of both Dorsal and Dif depends on Cactus protein |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA cytoplasm. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:8242747 Dif is normally localized in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. |
| GO:0005829 cytosol | IDA PMID:14585960 Discrete functions of TRAF1 and TRAF2 in Drosophila melanoga... | ACCEPT | Summary: Cytosolic Dif before DTRAF2-induced translocation. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:14585960 Ectopic expression of DTRAF2 induced nuclear translocation of two Drosophila NF-kappaBs, DIF and Relish, consequently activating the transcription of the antimicrobial peptide genes diptericin, diptericin-like protein, and drosomycin. |
| GO:0005829 cytosol | IDA PMID:8242747 Dif, a dorsal-related gene that mediates an immune response ... | ACCEPT | Summary: Cytoplasmic Dif in fat body. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:8242747 Dif is normally localized in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209295 | ACCEPT | Summary: Reactome Toll-pathway reaction placing the DL/DIF dimer in the cytosol. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:9510254 Cytoplasmic retention of both Dorsal and Dif depends on Cactus protein |
| GO:0005829 cytosol | TAS Reactome:R-DME-214857 | ACCEPT | Summary: Reactome Toll-pathway reaction placing the DL/DIF dimer in the cytosol. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:9510254 Cytoplasmic retention of both Dorsal and Dif depends on Cactus protein |
| GO:0005829 cytosol | TAS Reactome:R-DME-214860 | ACCEPT | Summary: Reactome Toll-pathway reaction placing the DL/DIF dimer in the cytosol. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:9510254 Cytoplasmic retention of both Dorsal and Dif depends on Cactus protein |
| GO:0005829 cytosol | TAS Reactome:R-DME-214864 | ACCEPT | Summary: Reactome Toll-pathway reaction placing the DL/DIF dimer in the cytosol. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:9510254 Cytoplasmic retention of both Dorsal and Dif depends on Cactus protein |
| GO:0005829 cytosol | TAS Reactome:R-DME-214871 | ACCEPT | Summary: Reactome Toll-pathway reaction placing the DL/DIF dimer in the cytosol. Reason: In the absence of signal Dif is retained in the cytoplasm by Cactus; a correct and regulatory location. Supporting Evidence: PMID:9510254 Cytoplasmic retention of both Dorsal and Dif depends on Cactus protein |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based regulation of DNA-templated transcription. Reason: Correct but general. Supporting Evidence: PMID:7621828 We now present evidence that the Dif gene product trans-activates the Drosophila Cecropin A1 gene in co-transfection assays. |
| GO:0006357 regulation of transcription by RNA polymerase II | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based regulation of transcription by RNA polymerase II. Reason: Correct but general; GO:0045944 is the specific term. Supporting Evidence: PMID:7621828 We now present evidence that the Dif gene product trans-activates the Drosophila Cecropin A1 gene in co-transfection assays. |
| GO:0006955 immune response | IMP PMID:17032737 The nucleoporin Nup214 sequesters CRM1 at the nuclear rim an... | KEEP AS NON CORE | Summary: Immune response (Nup214 study). Reason: Broad term; innate immune response and defense-response terms describe the role precisely. Supporting Evidence: PMID:17032737 overexpression of the Nup214-Nup88 complex trapped CRM1 and Dorsal to cytoplasmic foci and inhibited protein export and immune response activation. |
| GO:0006955 immune response | IMP PMID:24358857 Drosophila immune priming against Pseudomonas aeruginosa is ... | KEEP AS NON CORE | Summary: NF-kappaB-mediated responses contribute to immune priming against P. aeruginosa. Reason: Broad term; the priming phenotype is a secondary readout of Dif immune function. Supporting Evidence: PMID:24358857 not only the cellular, but also the systemic NF-ΞΊB-mediated immune responses contribute to immune priming. |
| GO:0007249 canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA canonical NF-kappaB signal transduction. Reason: GO:0007249 is defined as the IKK-dependent NF-kappaB cascade. Dif is released by signal-dependent degradation of Cactus, the conserved core of that cassette, but in the Toll branch drosomycin induction and Cactus degradation do not require the fly IKKbeta ird5, which is dedicated to Relish/Imd signalling. Broadly homologous, but the IKK clause is not met; GO:0008063 is the accurate term. Supporting Evidence: PMID:11156609 The ird5 phenotype and sequence suggest that the gene is specifically required for the activation of Relish, a Drosophila NF-kappaB family member. PMID:11156609 ird5/DmIkk Ξ² homozygous mutant females are fertile, demonstrating that this gene is not required for degradation of Cactus during dorsal-ventral patterning in the embryo. |
| GO:0007249 canonical NF-kappaB signal transduction | IDA PMID:7479760 Interactions of a Rel protein with its inhibitor. | KEEP AS NON CORE | Summary: Rel-Cactus interaction in yeast (abstract describes Dorsal). Reason: GO:0007249 is defined as the IKK-dependent NF-kappaB cascade. Dif is released by signal-dependent degradation of Cactus, the conserved core of that cassette, but in the Toll branch drosomycin induction and Cactus degradation do not require the fly IKKbeta ird5, which is dedicated to Relish/Imd signalling. Broadly homologous, but the IKK clause is not met; GO:0008063 is the accurate term. Supporting Evidence: PMID:11156609 The ird5 phenotype and sequence suggest that the gene is specifically required for the activation of Relish, a Drosophila NF-kappaB family member. |
| GO:0007249 canonical NF-kappaB signal transduction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA canonical NF-kappaB signal transduction. Reason: GO:0007249 is defined as the IKK-dependent NF-kappaB cascade. Dif is released by signal-dependent degradation of Cactus, the conserved core of that cassette, but in the Toll branch drosomycin induction and Cactus degradation do not require the fly IKKbeta ird5, which is dedicated to Relish/Imd signalling. Broadly homologous, but the IKK clause is not met; GO:0008063 is the accurate term. Supporting Evidence: PMID:11156609 The ird5 phenotype and sequence suggest that the gene is specifically required for the activation of Relish, a Drosophila NF-kappaB family member. |
| GO:0008063 Toll signaling pathway | IDA PMID:34576280 LncRNA-CR11538 Decoys Dif/Dorsal to Reduce Antimicrobial Pep... | ACCEPT | Summary: Dif acts downstream of Toll. Reason: Dif is the principal terminal transcription factor of the Drosophila Toll pathway in the adult immune response (PGRP-SA/GNBP1 or fungal sensing, Spaetzle, Toll, Myd88/Tube/Pelle, Cactus, Dif). GO:0008063 is the correct Drosophila-specific pathway term, distinct from vertebrate TLR pattern-recognition signalling. Supporting Evidence: PMID:34576280 lncRNA-CR11538 can decoy Dif/Dorsal away from the promoters of Drs and Mtk to repress their transcriptions by ChIP-qPCR and dual luciferase report experiments. |
| GO:0008063 Toll signaling pathway | IDA PMID:35379744 Interaction of lncRNA-CR33942 with Dif/Dorsal Facilitates An... | ACCEPT | Summary: Dif acts downstream of Toll. Reason: Dif is the principal terminal transcription factor of the Drosophila Toll pathway in the adult immune response (PGRP-SA/GNBP1 or fungal sensing, Spaetzle, Toll, Myd88/Tube/Pelle, Cactus, Dif). GO:0008063 is the correct Drosophila-specific pathway term, distinct from vertebrate TLR pattern-recognition signalling. Supporting Evidence: PMID:35379744 lncRNA-CR33942 interacts with the NF-ΞΊB transcription factors Dorsal-related immunity factor/Dorsal to promote the transcriptions of antimicrobial peptides drosomycin and metchnikowin |
| GO:0008063 Toll signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA Toll signaling pathway. Reason: Dif is the principal terminal transcription factor of the Drosophila Toll pathway in the adult immune response (PGRP-SA/GNBP1 or fungal sensing, Spaetzle, Toll, Myd88/Tube/Pelle, Cactus, Dif). GO:0008063 is the correct Drosophila-specific pathway term, distinct from vertebrate TLR pattern-recognition signalling. Supporting Evidence: PMID:10197979 We also demonstrate that Dif is a downstream component of the Toll signaling pathway in activating the drosomycin expression. |
| GO:0008063 Toll signaling pathway | IGI PMID:10843389 The Rel protein DIF mediates the antifungal but not the anti... | ACCEPT | Summary: Dif acts downstream of Toll. Reason: Dif is the principal terminal transcription factor of the Drosophila Toll pathway in the adult immune response (PGRP-SA/GNBP1 or fungal sensing, Spaetzle, Toll, Myd88/Tube/Pelle, Cactus, Dif). GO:0008063 is the correct Drosophila-specific pathway term, distinct from vertebrate TLR pattern-recognition signalling. Supporting Evidence: PMID:10843389 Genetic epistasis experiments demonstrate that Dif mediates the Toll-dependent control of the inducibility of the antifungal peptide gene Drosomycin. |
| GO:0008063 Toll signaling pathway | IGI PMID:28621429 The SUMO-targeted ubiquitin ligase, Dgrn, is essential for D... | ACCEPT | Summary: Dif acts downstream of Toll. Reason: Dif is the principal terminal transcription factor of the Drosophila Toll pathway in the adult immune response (PGRP-SA/GNBP1 or fungal sensing, Spaetzle, Toll, Myd88/Tube/Pelle, Cactus, Dif). GO:0008063 is the correct Drosophila-specific pathway term, distinct from vertebrate TLR pattern-recognition signalling. Supporting Evidence: PMID:28621429 Degringolade (Dgrn, CG10981), a SUMO-targeted ubiquitin ligase connecting the two pathways, is essential for the innate immunity response in Drosophila. |
| GO:0008063 Toll signaling pathway | IGI PMID:8242747 Dif, a dorsal-related gene that mediates an immune response ... | ACCEPT | Summary: Dif acts downstream of Toll. Reason: Dif is the principal terminal transcription factor of the Drosophila Toll pathway in the adult immune response (PGRP-SA/GNBP1 or fungal sensing, Spaetzle, Toll, Myd88/Tube/Pelle, Cactus, Dif). GO:0008063 is the correct Drosophila-specific pathway term, distinct from vertebrate TLR pattern-recognition signalling. Supporting Evidence: PMID:8242747 Dif is normally localized in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. |
| GO:0008063 Toll signaling pathway | IMP PMID:10197979 Toll receptor-mediated Drosophila immune response requires D... | ACCEPT | Summary: Dif acts downstream of Toll. Reason: Dif is the principal terminal transcription factor of the Drosophila Toll pathway in the adult immune response (PGRP-SA/GNBP1 or fungal sensing, Spaetzle, Toll, Myd88/Tube/Pelle, Cactus, Dif). GO:0008063 is the correct Drosophila-specific pathway term, distinct from vertebrate TLR pattern-recognition signalling. Supporting Evidence: PMID:10197979 We also demonstrate that Dif is a downstream component of the Toll signaling pathway in activating the drosomycin expression. |
| GO:0008063 Toll signaling pathway | IMP PMID:10369678 A mosaic analysis in Drosophila fat body cells of the contro... | ACCEPT | Summary: Dif acts downstream of Toll. Reason: Dif is the principal terminal transcription factor of the Drosophila Toll pathway in the adult immune response (PGRP-SA/GNBP1 or fungal sensing, Spaetzle, Toll, Myd88/Tube/Pelle, Cactus, Dif). GO:0008063 is the correct Drosophila-specific pathway term, distinct from vertebrate TLR pattern-recognition signalling. Supporting Evidence: PMID:10369678 in the absence of both genes, the immune-inducibility of drosomycin is lost but can be rescued by overexpression of either dorsal or dif under the control of a heat-shock promoter. |
| GO:0010628 positive regulation of gene expression | IGI PMID:19221590 Short-term starvation of immune deficient Drosophila improve... | KEEP AS NON CORE | Summary: Under starvation Dif activates Cytochrome C oxidase expression, raising NO. Reason: Genetic evidence that Dif is needed for an NO-generating response in relish mutants; a context-specific, indirect readout of its transcriptional activity. Supporting Evidence: PMID:19221590 Surprisingly, NO signalling required the NF-kappaB protein Dif, usually needed for responses against Gram-positive bacteria. PMID:19221590 In the absence of Relish, STS stimulated the Toll pathway where Dif activated Cytochrome Oxidase C (CCO), which in turn elevated NO levels without NOS upregulation. |
| GO:0034097 response to cytokine | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA response to cytokine. Reason: Dif acts downstream of the cytokine Spaetzle, so the term is formally true but vague; Toll signaling pathway captures it precisely. Supporting Evidence: PMID:10197979 We also demonstrate that Dif is a downstream component of the Toll signaling pathway in activating the drosomycin expression. |
| GO:0035070 salivary gland histolysis | IMP PMID:11973616 AP-1, but not NF-kappa B, is required for efficient steroid-... | REMOVE | Summary: Dif is induced before salivary gland death, but Rel/NF-kappaB null mutants have no effect on histolysis. Reason: The cited paper reports the opposite of the annotation: null mutations in all three Drosophila Rel genes, alone or in combination, have no apparent effect on steroid-triggered salivary gland cell death, which instead requires AP-1 (Dfos). Dif expression in the dying gland is correlative. The abstract states this directly, so this is a contradicted function rather than an unverifiable one. Supporting Evidence: PMID:11973616 We show that null mutations in the three Drosophila Rel/NF-kappa B family members, either alone or in combination, have no apparent effect on this death response. PMID:11973616 This study demonstrates a role for AP-1 in the stage-specific steroid-triggered programmed cell death of larval tissues during Drosophila metamorphosis. |
| GO:0035206 regulation of hemocyte proliferation | IDA PMID:17060622 Rel/NF-kappaB double mutants reveal that cellular immunity i... | KEEP AS NON CORE | Summary: Dif/Dorsal control blood cell number in the hemocyte lineage. Reason: Dif and Dorsal act in the hemocyte lineage to promote blood cell number and proliferation; supported, but a secondary role mediated by transcriptional control. Supporting Evidence: PMID:17060622 mutants that lack the Drosophila Rel/NF-kappaB proteins Dorsal and Dif have very few blood cells PMID:17060622 Dif and Dorsal also act in blood cells to promote proliferation. |
| GO:0035206 regulation of hemocyte proliferation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA regulation of hemocyte proliferation. Reason: Dif and Dorsal act in the hemocyte lineage to promote blood cell number and proliferation; supported, but a secondary role mediated by transcriptional control. Supporting Evidence: PMID:17060622 Dif and Dorsal also act in blood cells to promote proliferation. |
| GO:0038061 non-canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | REMOVE | Summary: IBA non-canonical NF-kappaB signal transduction. Reason: GO:0038061 is defined by NIK/IKKalpha-dependent processing of p100 to p52. Dif is a class II Rel protein without a processable ankyrin-repeat precursor domain, it is activated by release from Cactus, and Toll-branch activation does not require the fly IKK ird5. The term is propagated from vertebrate RelB/NFKB2 and does not apply to Dif. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000652441 Β· PTN000652441 SUPPORTS SOURCE BUT NOT TARGET The node carries the NIK/p100-processing pathway supported by vertebrate Rel members; Dif is released from the IkappaB Cactus rather than generated by precursor processing, and its Toll-branch activation does not require the fly IKKbeta ird5. Supporting Evidence: PMID:11156609 The ird5 phenotype and sequence suggest that the gene is specifically required for the activation of Relish, a Drosophila NF-kappaB family member. PMID:9510254 Cytoplasmic retention of both Dorsal and Dif depends on Cactus protein |
| GO:0045087 innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: IBA innate immune response. Reason: Dif is a central effector of Toll-dependent innate immunity against fungi and Gram-positive bacteria. Supporting Evidence: PMID:10843389 In Drosophila, Dif appears to be dedicated to the antifungal defense elicited by fungi and gram-positive bacteria. |
| GO:0045087 innate immune response | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA innate immune response. Reason: Dif is a central effector of Toll-dependent innate immunity against fungi and Gram-positive bacteria. Supporting Evidence: PMID:10843389 In Drosophila, Dif appears to be dedicated to the antifungal defense elicited by fungi and gram-positive bacteria. |
| GO:0045087 innate immune response | IMP PMID:10197979 Toll receptor-mediated Drosophila immune response requires D... | ACCEPT | Summary: Dif is required for Toll-mediated induction of drosomycin and defensin. Reason: Dif is a central effector of Toll-dependent innate immunity against fungi and Gram-positive bacteria. Supporting Evidence: PMID:10197979 We also demonstrate that Dif is a downstream component of the Toll signaling pathway in activating the drosomycin expression. PMID:10197979 The results show that the presence of Dif without Dorsal is sufficient to mediate the induction of drosomycin and defensin. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA positive regulation of transcription by RNA polymerase II. Reason: Dif activates RNA polymerase II transcription of Toll-pathway target genes (drosomycin, Cecropin A1, metchnikowin). Core process. Supporting Evidence: PMID:7621828 We now present evidence that the Dif gene product trans-activates the Drosophila Cecropin A1 gene in co-transfection assays. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:12230549 An intron enhancer activates the immunoglobulin-related Hemo... | ACCEPT | Summary: Dif transactivates the Hemolin intron enhancer in S2 cells. Reason: Dif activates RNA polymerase II transcription of Toll-pathway target genes (drosomycin, Cecropin A1, metchnikowin). Core process. Supporting Evidence: PMID:12230549 Co-transfections of Drosophila SL2 cells showed that the Drosophila Rel factor Dif (Dorsal-related immunity factor), transactivates reporter gene constructs through the intron. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:12556495 Signal-induced transcriptional activation by Dif requires th... | ACCEPT | Summary: Dif-driven drosomycin activation requires the dTRAP80 Mediator module. Reason: Dif activates RNA polymerase II transcription of Toll-pathway target genes (drosomycin, Cecropin A1, metchnikowin). Core process. Supporting Evidence: PMID:12556495 activation of Drosophila antimicrobial peptide drosomycin gene expression by the NF-kappa B-like transcription factor Dif during induction of the Toll signaling pathway was dependent on the dTRAP80 module. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:34576280 LncRNA-CR11538 Decoys Dif/Dorsal to Reduce Antimicrobial Pep... | ACCEPT | Summary: Dif/Dorsal occupy and activate Drs and Mtk promoters. Reason: Dif activates RNA polymerase II transcription of Toll-pathway target genes (drosomycin, Cecropin A1, metchnikowin). Core process. Supporting Evidence: PMID:34576280 lncRNA-CR11538 can decoy Dif/Dorsal away from the promoters of Drs and Mtk to repress their transcriptions by ChIP-qPCR and dual luciferase report experiments. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:7479760 Interactions of a Rel protein with its inhibitor. | ACCEPT | Summary: Rel transcriptional activation in yeast (abstract describes Dorsal). Reason: Dif activates RNA polymerase II transcription of Toll-pathway target genes (drosomycin, Cecropin A1, metchnikowin). Core process. Abstract-only record; deferred to the curator. Supporting Evidence: PMID:7621828 We now present evidence that the Dif gene product trans-activates the Drosophila Cecropin A1 gene in co-transfection assays. |
| GO:0048935 peripheral nervous system neuron development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA peripheral nervous system neuron development. Reason: Dif mutants show ectopic bristles; Rel proteins regulate scute in sensory organ precursor selection. Supported but peripheral. Supporting Evidence: PMID:18000549 Flies homozygous for loss of function alleles of dl, Dif and Rel were found to display ectopic bristles on the notum in dorsocentral, scutellar and lateral regions |
| GO:0048935 peripheral nervous system neuron development | IMP PMID:18000549 NF-kappaB/Rel-mediated regulation of the neural fate in Dros... | KEEP AS NON CORE | Summary: Ectopic bristles in Dif mutants. Reason: Dif mutants show ectopic bristles; Rel proteins regulate scute in sensory organ precursor selection. Supported but peripheral. Supporting Evidence: PMID:18000549 Flies homozygous for loss of function alleles of dl, Dif and Rel were found to display ectopic bristles on the notum in dorsocentral, scutellar and lateral regions PMID:18000549 these factors regulate transcription of scute during the singling out of sensory organ precursors |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:10843389 The Rel protein DIF mediates the antifungal but not the anti... | ACCEPT | Summary: Dif is dedicated to defence elicited by fungi and Gram-positive bacteria. Reason: Dif mutants, like Toll-pathway mutants, are highly susceptible to Gram-positive bacterial infection; Dif is required for this defence. Supporting Evidence: PMID:10843389 In Drosophila, Dif appears to be dedicated to the antifungal defense elicited by fungi and gram-positive bacteria. |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:11823479 Cutting edge: the toll pathway is required for resistance to... | ACCEPT | Summary: Toll pathway (including Dif) is required for resistance to Gram-positive bacteria. Reason: Dif mutants, like Toll-pathway mutants, are highly susceptible to Gram-positive bacterial infection; Dif is required for this defence. Supporting Evidence: PMID:11823479 we report that the Toll pathway, but not that of immune deficiency, is required for resistance to other Gram-positive bacteria and that this response does not involve Defensin. |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:14684822 Dual activation of the Drosophila toll pathway by two patter... | ACCEPT | Summary: PGRP-SA/GNBP1 activation of Toll for Gram-positive defence; Dif mutants used as pathway controls. Reason: Dif mutants, like Toll-pathway mutants, are highly susceptible to Gram-positive bacterial infection; Dif is required for this defence. The abstract-only record does not name Dif; the curator is deferred to. Supporting Evidence: PMID:14684822 Our results demonstrate that GNBP1 and PGRP-SA can jointly activate the Toll pathway. PMID:10843389 In Drosophila, Dif appears to be dedicated to the antifungal defense elicited by fungi and gram-positive bacteria. |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:19221590 Short-term starvation of immune deficient Drosophila improve... | ACCEPT | Summary: dif flies die rapidly after Enterococcus faecalis infection. Reason: Dif mutants, like Toll-pathway mutants, are highly susceptible to Gram-positive bacterial infection; Dif is required for this defence. Supporting Evidence: PMID:19221590 STS dif flies infected with the Gram-positive bacterium Enterococcus faecalis showed similarly high levels of susceptibility to infection as their AL siblings and died rapidly after septic injury |
| GO:0050832 defense response to fungus | IMP PMID:10843389 The Rel protein DIF mediates the antifungal but not the anti... | ACCEPT | Summary: Dif mutants are susceptible to fungal infection. Reason: Dif is required for the Toll-dependent antifungal response in adults. Supporting Evidence: PMID:10843389 Like mutants of the Toll pathway, Dif mutant flies are susceptible to fungal but not to bacterial infections. PMID:10843389 DIF alone is required for the antifungal response in adults, but is redundant in larvae with Dorsal |
| GO:0050832 defense response to fungus | IMP PMID:14684822 Dual activation of the Drosophila toll pathway by two patter... | ACCEPT | Summary: Antifungal defence (Toll pathway study; abstract does not name Dif). Reason: Dif is required for the Toll-dependent antifungal response in adults. Deferred to the curator. Supporting Evidence: PMID:10843389 Like mutants of the Toll pathway, Dif mutant flies are susceptible to fungal but not to bacterial infections. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Wu and Anderson (1998) reported that Toll is not required for larval Dif nuclear import, whereas later genetics place Dif downstream of Toll for drosomycin. Which upstream pathway controls Dif import in larval fat body?
Q: Should the Toll-Cactus-Dif branch carry canonical NF-kappaB signal transduction (GO:0007249), whose definition requires IKK, given that drosomycin induction is ird5/IKKbeta-independent?
Q: How much of adult antimicrobial peptide induction is carried by Dif-Relish heterodimers in vivo, as opposed to Dif homodimers?
Experiment: Compare Dif ChIP-seq in adult fat body after fungal versus Gram-positive infection, and in relish mutants, to separate homodimer and Dif-Relish heterodimer targets.
Experiment: Test Dif nuclear import in larval fat body of Toll and pelle null clones to resolve the Toll-independent import reported in larvae.
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Download this section (compressed HTML)Dorsal-related immunity factor (Dif) encodes a transcription factor that contributes to zygotic function of the Toll pathway, notably the regulation of antimicrobial peptides, but it is not involved in dorsoventral patterning of the embryo.
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