title: Innate immune signaling inDrosophilais regulated by transforming growth factor β (TGFβ)-activated kinase (Tak1)-triggered ubiquitin editing.
abstract: Coordinated regulation of innate immune responses is necessary in all metazoans. InDrosophilathe Imd pathway detects Gram-negative bacterial infections through recognition of diaminopimelic acid (DAP)-type peptidoglycan and activation of the NF-κB precursor Relish, which drives robust antimicrobial peptide gene expression. Imd is a receptor-proximal adaptor protein homologous to mammalian RIP1 that is regulated by proteolytic cleavage and Lys-63-polyubiquitination. However, the precise events and molecular mechanisms that control the post-translational modification of Imd remain unclear. Here, we demonstrate that Imd is rapidly Lys-63-polyubiquitinated at lysine residues 137 and 153 by the sequential action of two E2 enzymes, Ubc5 and Ubc13-Uev1a, in conjunction with the E3 ligase Diap2. Lys-63-ubiquitination activates the TGFβ-activated kinase (Tak1), which feeds back to phosphorylate Imd, triggering the removal of Lys-63 chains and the addition of Lys-48 polyubiquitin. This ubiquitin-editing process results in the proteasomal degradation of Imd, which we propose functions to restore homeostasis to theDrosophilaimmune response.
authors.affiliation: From the Division of Infectious Disease, Department of Medicine and.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: From the Division of Infectious Disease, Department of Medicine and.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Paquette
authors.affiliation: From the Division of Infectious Disease, Department of Medicine and.
authors.forename: Shahan
authors.initials: S
authors.lastname: Mamoor
authors.affiliation: From the Division of Infectious Disease, Department of Medicine and.
authors.forename: Florentina
authors.initials: F
authors.lastname: Rus
authors.affiliation: From the Division of Infectious Disease, Department of Medicine and.
authors.forename: Anubhab
authors.initials: A
authors.lastname: Nandy
authors.affiliation: the Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: John
authors.initials: J
authors.lastname: Leszyk
authors.affiliation: the Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaffer
authors.affiliation: From the Division of Infectious Disease, Department of Medicine and neal.silverman@umassmed.edu.
authors.forename: Neal
authors.initials: N
authors.lastname: Silverman
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000276:immunology*; D004331:Drosophila melanogaster; D007113:Immunity, Innate; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology*; D025821:Polyubiquitin / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000276:immunology; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology*
chemical_list: C111892:DIAP2 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; C101626:Rel protein, Drosophila; D014157:Transcription Factors; C439909:imd protein, Drosophila; D025821:Polyubiquitin; D044763:Ubiquitin-Conjugating Enzymes; C583339:Uev1a protein, Drosophila; D020930:MAP Kinase Kinase Kinases; C000593602:TAK1 protein, Drosophila
keywords: Drosophila; Imd; NF-κB (NF-κB); Tak1; antimicrobial peptide (AMP); mass spectrometry (MS); phosphorylation; ubiquitin editing; ubiquitylation (ubiquitination)