Hyd ubiquitinates the NF-κB co-factor Akirin to operate an effective immune response in Drosophila

Autor: Adrian Acker, Akira Goto, Michael Boutros, Marie-Odile Fauvarque, Alexandre Cammarata-Mouchtouris, Xuan-Hung Nguyen, Jean-Marc Reichhart, François Bonnay, Nicolas Matt, Amir Orian
Přispěvatelé: Modèles Insectes de l'Immunité Innée (M3I), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vietnam National University [Hanoï] (VNU), Austrian Academy of Sciences (OeAW), Technion - Israel Institute of Technology [Haifa], Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Heidelberg University, This work was supported by the Centre National de la Recherche Scientifique (http://www.cnrs.fr/fr/page-daccueil) in the frame of the LIA «REL2 and resistance to malaria». This work was performed under the framework of the LABEX: ANR-10- LABX-0036_NETRNA and ANR-17-EURE-0023, through a funding of the state managed by the French National Research Agency (https://anr.fr/) as part of the Investments for the future program and also from a European Research Council (https://erc.europa.eu/) Advanced Grant (AdG_20090506 ‘‘Immudroso,’’ to J.-M.R.). Generation of RNAi reagents by M.B. was supported by DFG DRiC (https://www.dfg.de/). N. M. is a Fellow at the University of Strasbourg Institute for Advanced Study (USIAS-2018-073, ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-17-EURE-0023,IMCBio,Integrative Molecular and Cellular Biology(2017), European Project: 250076,EC:FP7:ERC,ERC-2009-AdG,IMMUDROSO(2010), Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-IDEX-0002,UNISTRA,Network of regulatory RNAs across kingdoms and dynamical responses to biotic and abiotic stresses.(2010), Bodescot, Myriam, Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, Integrative Molecular and Cellular Biology - - IMCBio2017 - ANR-17-EURE-0023 - EURE - VALID, Sensing and Signalling in the Innate Immune Response, using Drosophila as a Model. - IMMUDROSO - - EC:FP7:ERC2010-03-01 - 2015-02-28 - 250076 - VALID
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Biochemistry
Ligases
chemistry.chemical_compound
Ubiquitin
Transcription (biology)
Medicine and Health Sciences
Drosophila Proteins
Small interfering RNAs
Biology (General)
Immune Response
0303 health sciences
biology
Drosophila Melanogaster
030302 biochemistry & molecular biology
Nuclear Proteins
Eukaryota
[SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular Networks [q-bio.MN]
Animal Models
Cell biology
Ubiquitin ligase
Enzymes
Insects
Nucleic acids
Experimental Organism Systems
Drosophila
Signal transduction
Drosophila melanogaster
Research Article
Arthropoda
QH301-705.5
Ubiquitin-Protein Ligases
DNA transcription
Immunology
Research and Analysis Methods
Microbiology
03 medical and health sciences
Model Organisms
Virology
Gram-Negative Bacteria
DNA-binding proteins
Genetics
Animals
Humans
Non-coding RNA
Molecular Biology
Transcription factor
030304 developmental biology
Innate immune system
Ubiquitination
Organisms
Biology and Life Sciences
Proteins
NF-κB
RC581-607
biology.organism_classification
Ubiquitin Ligases
Invertebrates
Immunity
Innate
Gene regulation
Regulatory Proteins
chemistry
[SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular Networks [q-bio.MN]
biology.protein
Animal Studies
Enzymology
RNA
Parasitology
Gene expression
Immunologic diseases. Allergy
HeLa Cells
Transcription Factors
Zdroj: PLoS Pathogens
PLoS Pathogens, 2020, 16 (4), pp.e1008458. ⟨10.1371/journal.ppat.1008458⟩
PLoS Pathogens, Public Library of Science, 2020, 16 (4), pp.e1008458. ⟨10.1371/journal.ppat.1008458⟩
PLoS Pathogens, Vol 16, Iss 4, p e1008458 (2020)
ISSN: 1553-7366
1553-7374
DOI: 10.1371/journal.ppat.1008458⟩
Popis: The Immune Deficiency (IMD) pathway in Drosophila melanogaster is activated upon microbial challenge with Gram-negative bacteria to trigger the innate immune response. In order to decipher this nuclear factor κB (NF-κB) signaling pathway, we undertook an in vitro RNAi screen targeting E3 ubiquitin ligases specifically and identified the HECT-type E3 ubiquitin ligase Hyperplastic discs (Hyd) as a new actor in the IMD pathway. Hyd mediated Lys63 (K63)-linked polyubiquitination of the NF-κB cofactor Akirin was required for efficient binding of Akirin to the NF-κB transcription factor Relish. We showed that this Hyd-dependent interaction was required for the transcription of immunity-related genes that are activated by both Relish and Akirin but was dispensable for the transcription of genes that depend solely on Relish. Therefore Hyd is key in NF-κB transcriptional selectivity downstream of the IMD pathway. Drosophila depleted of Akirin or Hyd failed to express the full set of genes encoding immune-induced anti-microbial peptides and succumbed to immune challenges. We showed further that UBR5, the mammalian homolog of Hyd, was also required downstream of the NF-κB pathway for the activation of Interleukin 6 (IL6) transcription by LPS or IL-1β in cultured human cells. Our findings link the action of an E3 ubiquitin ligase to the activation of immune effector genes, deepening our understanding of the involvement of ubiquitination in inflammation and identifying a potential target for the control of inflammatory diseases.
Author summary Ubiquitination has been recently identified in pathogenesis and progression of various diseases where inflammation is critical. NF-κB transcription factors are key actors in the transcriptional cascade leading to inflammation as they activate genes with pro- or anti-inflammatory activities. The similarity between the immune pathways in flies and mammals makes Drosophila melanogaster an excellent model to study the innate response. Accordingly, we decided to identify E3 ubiquitin-ligases involved in the regulation of NF-κB pathway, using Drosophila as a model system. A RNAi based screen in immortalized embryonic macrophage-like Drosophila cells points to the HECT-E3 ubiquitin ligase Hyd as a new regulator of the Immune-deficiency (IMD) NF-κB pathway, activated after Gram-negative immune challenge. More precisely, we showed that Hyd acts at the level of Akirin, an evolutionarily conserved player in the NF-κB pathway, required for the transcription of pro-inflammatory genes, but not for the NF-κB-dependent genes contributing to the down-regulation of inflammation. In addition, we could show that the human homologue of Hyd (UBR5) acts genetically at the level of human AKIRIN2, pointing to a unique dichotomy between Hyd/Akirin-dependent and -independent gene activation, allowing for the decoupling activation and resolution of inflammation. These results identified UBR5 as a putative target for anti-inflammatory compounds.
Databáze: OpenAIRE
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