Journal Article

Protein phosphatase 1 subunit Ppp1r15a/GADD34 regulates cytokine production in polyinosinic:polycytidylic acid-stimulated dendritic cells

Wenger, Till, Pierre, Philippe, Schmidt, Enrico K, Couderc, Thérèse, Ceppi, Maurizio, Terawaki, Seigo, Clavarino, Giovanna, Gatti, Evelina, Chasson, Lionel, Cláudio, Nuno, Dalet, Alexandre, Lecuit, Marc

2012

Overview

In response to inflammatory stimulation, dendritic cells (DCs) have a remarkable pattern of differentiation that exhibits specific mechanisms to control the immune response. Here we show that in response to polyriboinosinic:polyribocytidylic acid (pI:C), DCs mount a specific integrated stress response during which the transcription factor ATF4 and the growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), a phosphatase 1 (PP1) cofactor, are expressed. In agreement with increased GADD34 levels, an extensive dephosphorylation of the translation initiation factor eIF2α was observed during DC activation. Unexpectedly, although DCs display an unusual resistance to protein synthesis inhibition induced in response to cytosolic dsRNA, GADD34 expression did not have a major impact on protein synthesis. GADD34, however, was shown to be required for normal cytokine production both in vitro and in vivo. These observations have important implications in linking further pathogen detection with the integrated stress response pathways.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Activating transcription factor 4 / Activating Transcription Factor 4 - metabolism / Animals / Biological Sciences / Cell activation / Cells / Cofactors / Cytokines / Cytokines - biosynthesis / Cytosol - drug effects / Cytosol - metabolism / Dendritic cells / Dendritic Cells - drug effects / Dendritic Cells - enzymology / Dephosphorylation / Differentiation / DNA / DNA damage / Double stranded RNA / eIF-2 Kinase - metabolism / Enzyme Activation - drug effects / Eukaryotic Initiation Factor-2 - metabolism / GADD34 protein / Immune response / Immunology / Inflammation / Interferon-beta - metabolism / Life Sciences / Macrophages / Messenger RNA / Mice / Natural killer cells / Oxidative stress / Pathogens / Phosphatases / Phosphoprotein phosphatase / Phosphorylation / Phosphorylation - drug effects / Poly I-C - pharmacology / Protein biosynthesis / Protein Biosynthesis - drug effects / Protein Phosphatase 1 - metabolism / Protein Subunits - metabolism / Protein synthesis / Stress / stress response / transcription factors / Translation initiation factor eIF2a / Up-Regulation - drug effects