| Title: |
Protein synthesis inhibition and GADD34 control IFN‐β heterogeneous expression in response to dsRNA |
| Authors: |
Dalet, Alexandre; Argüello, Rafael J; Combes, Alexis; Spinelli, Lionel; Jaeger, Sebastien; Fallet, Mathieu; Vu Manh, Thien‐phong; Mendes, Andreia; Perego, Jessica; Reverendo, Marisa; Camosseto, Voahirana; Dalod, Marc; Weil, Tobias; Santos, Manuel A; Gatti, Evelina; Pierre, Philippe |
| Contributors: |
Centre d'Immunologie de Marseille - Luminy (CIML); Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Institute for Research in Biomedicine (iBiMED); Universidade de Aveiro = University of Aveiro; ANR-10-BLAN-1236,MARCHxIRAP,Rôle de l'ubiquitination dans la régulation du trafic intracellulaire des molécules de classe I du CMH et la présentation croisée(2010); ANR-10-BLAN-1308,BRUTir,Impact de l'infection et de la capture de Brucella sur la fonction des cellules dendritiques et l'immunité(2010); ANR-12-BSV2-0025,STRESSOR,Impact de la phosphorylation du facteur d'initiation de traduction eIF2-a pendant l'exposition au stress(2012); ANR-12-ISV3-0002,MISTRAL,Conséquences du contrôle réciproque de l'infidélité de la traduction dans l'immunité anti-fongique(2012); ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011); ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010); ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010); European Project: 281225,ERC-2011-StG_20101109,ERC-2011-StG_20101109,SYSTEMSDENDRITIC(2012) |
| Source: |
ISSN: 0261-4189. |
| Publisher Information: |
CCSD; EMBO Press |
| Publication Year: |
2017 |
| Collection: |
Aix-Marseille Université: HAL |
| Subject Terms: |
Immunology; Stress granules; RIG-I-like receptors; Puromycin; Integrated stress response; CGAMP; [SDV.IMM]Life Sciences [q-bio]/Immunology; [SDV.BC]Life Sciences [q-bio]/Cellular Biology |
| Description: |
International audience ; In innate immune responses, induction of type-I interferons (IFNs) prevents virus spreading while viral replication is delayed by protein synthesis inhibition. We asked how cells perform these apparently contradictory activities. Using single fibroblast monitoring by flow cytometry and mathematical modeling, we demonstrate that type-I IFN production is linked to cell's ability to enter dsRNA-activated PKR-dependent translational arrest and then overcome this inhibition by decreasing eIF2a phosphorylation through phosphatase 1c cofactor GADD34 (Ppp1r15a) expression. GADD34 expression, shown here to be dependent on the IRF3 transcription factor, is responsible for a biochemical cycle permitting pulse of IFN synthesis to occur in cells undergoing protein synthesis inhibition. Translation arrest is further demonstrated to be key for anti-viral response by acting synergistically with MAVS activation to amplify TBK1 signaling and IFN-b mRNA transcription , while GADD34-dependent protein synthesis recovery contributes to the heterogeneous expression of IFN observed in dsRNA-activated cells. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/28100675; info:eu-repo/grantAgreement//281225/EU/Harnessing systems immunology to unravel dendritic cell subset biology/SYSTEMSDENDRITIC; PUBMED: 28100675 |
| DOI: |
10.15252/embj.201695000 |
| Availability: |
https://amu.hal.science/hal-01476255; https://amu.hal.science/hal-01476255v1/document; https://amu.hal.science/hal-01476255v1/file/761.full_HAL.pdf; https://doi.org/10.15252/embj.201695000 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.8DB4DBAE |
| Database: |
BASE |