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

作者：Clavarino Giovanna; Claudio Nuno; Dalet Alexandre; Terawaki Seigo; Couderc Therese; Chasson Lionel; Ceppi Maurizio; Schmidt Enrico K; Wenger Till; Lecuit Marc; Gatti Evelina^*; Pierre Philippe

来源：Proceedings of the National Academy of Sciences, 2012, 109(8): 3006-3011.

DOI：10.1073/pnas.1104491109

• type-I interferon
• Toll-like receptor
• protein kinase RNA activated
• puromycin
• unfolded protein response

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 eIF2 alpha 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.

• 出版日期2012-2-21