Dephosphorylation of the RNA Sensors RIG-I and MDA5 by the Phosphatase PP1 Is Essential for Innate Immune Signaling
| Autor: | Michaela U. Gack, Shenghua Zhou, Robert W. Finberg, Kan Chen, Effi Wies, Natalya P. Maharaj, May K. Wang |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Interferon-Induced Helicase
IFIH1 Picornavirus viruses Immunoblotting Molecular Sequence Data Immunology Cell Line DEAD-box RNA Helicases Dephosphorylation Mice 03 medical and health sciences 0302 clinical medicine Interferon RNA interference Protein Phosphatase 1 Chlorocebus aethiops medicine Animals Humans Immunology and Allergy Phosphorylation Receptors Immunologic Vero Cells Cells Cultured 030304 developmental biology Mice Knockout 0303 health sciences Microscopy Confocal biology RIG-I virus diseases RNA RNA virus MDA5 Interferon-beta biology.organism_classification Virology Immunity Innate 3. Good health HEK293 Cells Infectious Diseases 030220 oncology & carcinogenesis Mutation DEAD Box Protein 58 RNA Viral RNA Interference HeLa Cells Signal Transduction medicine.drug |
| Zdroj: | Immunity. (3):437-449 |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2012.11.018 |
| Popis: | SummaryRIG-I and MDA5 have emerged as key cytosolic sensors for the detection of RNA viruses and lead to antiviral interferon (IFN) production. Recent studies have highlighted the importance of posttranslational modifications for controlling RIG-I antiviral activity. However, the regulation of MDA5 signal-transducing ability remains unclear. Here, we show that MDA5 signaling activity is regulated by a dynamic balance between phosphorylation and dephosphorylation of its caspase recruitment domains (CARDs). Employing a phosphatome RNAi screen, we identified PP1α and PP1γ as the primary phosphatases that are responsible for MDA5 and RIG-I dephosphorylation and that lead to their activation. Silencing of PP1α and PP1γ enhanced RIG-I and MDA5 CARD phosphorylation and reduced antiviral IFN-β production. PP1α- and PP1γ-depleted cells were impaired in their ability to induce IFN-stimulated gene expression, which resulted in enhanced RNA virus replication. This work identifies PP1α and PP1γ as regulators of antiviral innate immune responses to various RNA viruses, including influenza virus, paramyxovirus, dengue virus, and picornavirus. |
| Databáze: | OpenAIRE |
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