Please use this identifier to cite or link to this item:
Title: Protein synthesis inhibition and GADD34 control IFN-β heterogeneous expression in response to dsRNA
Author: Dalet, Alexandre
Argüello, Rafael J.
Combes, Alexis
Spinelli, Lionel
Jaeger, Sebastien
Fallet, Mathieu
Manh, Thien-Phong Vu
Mendes, Andreia
Perego, Jessica
Reverendo, Marisa
Camosseto, Voahirana
Dalod, Marc
Weil, Tobias
Santos, Manuel A.
Gatti, Evelina
Pierre, Philippe
Keywords: RIG-I-like receptors
Integrated stress response
Stress granules
Issue Date: 15-Mar-2017
Publisher: EMBO Press
Abstract: 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 eIF2α 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-β mRNA transcription, while GADD34-dependent protein synthesis recovery contributes to the heterogeneous expression of IFN observed in dsRNA-activated cells.
Peer review: yes
DOI: 10.15252/embj.201695000
ISSN: 0261-4189
Appears in Collections:IBIMED - Artigos

Files in This Item:
File Description SizeFormat 
Pierre EMBOj2017 GADD34 and IFNb.pdf4.02 MBAdobe PDFrestrictedAccess

Formato BibTex MendeleyEndnote Degois 

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.