title: Loss of Trabid, a new negative regulator of the drosophila immune-deficiency pathway at the level of TAK1, reduces life span.
abstract: A relatively unexplored nexus in Drosophila Immune deficiency (IMD) pathway is TGF-beta Activating Kinase 1 (TAK1), which triggers both immunity and apoptosis. In a cell culture screen, we identified that Lysine at position 142 was a K63-linked Ubiquitin acceptor site for TAK1, required for signalling. Moreover, Lysine at position 156 functioned as a K48-linked Ubiquitin acceptor site, also necessary for TAK1 activity. The deubiquitinase Trabid interacted with TAK1, reducing immune signalling output and K63-linked ubiquitination. The three tandem Npl4 Zinc Fingers and the catalytic Cysteine at position 518 were required for Trabid activity. Flies deficient for Trabid had a reduced life span due to chronic activation of IMD both systemically as well as in their gut where homeostasis was disrupted. The TAK1-associated Binding Protein 2 (TAB2) was linked with the TAK1-Trabid interaction through its Zinc finger domain that pacified the TAK1 signal. These results indicate an elaborate and multi-tiered mechanism for regulating TAK1 activity and modulating its immune signal.
authors.affiliation: Genes and Development Laboratory, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Merennege Dilan Anush
authors.initials: MD
authors.lastname: Fernando
authors.affiliation: Genes and Development Laboratory, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Ilias
authors.initials: I
authors.lastname: Kounatidis
authors.affiliation: Genes and Development Laboratory, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Petros
authors.initials: P
authors.lastname: Ligoxygakis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004330:Drosophila / Q000235:genetics* / Q000276:immunology; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D010450:Endopeptidases / Q000235:genetics*; D008239:Lysine / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D025801:Ubiquitin; D064570:Ubiquitin-Specific Proteases / Q000235:genetics*; D054875:Ubiquitination / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D016328:NF-kappa B; D025801:Ubiquitin; C439909:imd protein, Drosophila; D020930:MAP Kinase Kinase Kinases; C000593602:TAK1 protein, Drosophila; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases; C000593601:trbd protein, Drosophila; D008239:Lysine