title: Dephosphorylation of the RNA sensors RIG-I and MDA5 by the phosphatase PP1 is essential for innate immune signaling.
abstract: RIG-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.
authors.affiliation: Microbiology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, MA 01772-9102, USA.
authors.forename: Effi
authors.initials: E
authors.lastname: Wies
authors.forename: May K
authors.initials: MK
authors.lastname: Wang
authors.forename: Natalya P
authors.initials: NP
authors.lastname: Maharaj
authors.forename: Kan
authors.initials: K
authors.lastname: Chen
authors.forename: Shenghua
authors.initials: S
authors.lastname: Zhou
authors.forename: Robert W
authors.initials: RW
authors.lastname: Finberg
authors.forename: Michaela U
authors.initials: MU
authors.lastname: Gack
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D015151:Immunoblotting; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014709:Vero Cells
chemical_list: D012367:RNA, Viral; D011971:Receptors, Immunologic; D016899:Interferon-beta; D054645:Protein Phosphatase 1; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1