title: Antagonism of the phosphatase PP1 by the measles virus V protein is required for innate immune escape of MDA5.
abstract: The cytosolic sensor MDA5 is crucial for antiviral innate immune defense against various RNA viruses including measles virus; as such, many viruses have evolved strategies to antagonize the antiviral activity of MDA5. Here, we show that measles virus escapes MDA5 detection by targeting the phosphatases PP1α and PP1γ, which regulate MDA5 activity by removing an inhibitory phosphorylation mark. The V proteins of measles virus and the related paramyxovirus Nipah virus interact with PP1α/γ, preventing PP1-mediated dephosphorylation of MDA5 and thereby its activation. The PP1 interaction with the measles V protein is mediated by a conserved PP1-binding motif in the C-terminal region of the V protein. A recombinant measles virus expressing a mutant V protein deficient in PP1 binding is unable to antagonize MDA5 and is growth impaired due to its inability to suppress interferon induction. This identifies PP1 antagonism as a mechanism employed by paramyxoviruses for evading innate immune recognition.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Microbiology Division, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Davis
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Microbiology Division, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
authors.forename: May K
authors.initials: MK
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Rennick
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Full
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gableske
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Annelies W
authors.initials: AW
authors.lastname: Mesman
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Gringhuis
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: W Paul
authors.initials: WP
authors.lastname: Duprex
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Microbiology Division, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA. Electronic address: michaela_gack@hms.harvard.edu.
authors.forename: Michaela U
authors.initials: MU
authors.lastname: Gack
mesh_terms: D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D000072640:Interferon-Induced Helicase, IFIH1; D008459:Measles virus / Q000276:immunology* / Q000502:physiology*; D045405:Nipah Virus / Q000276:immunology / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors*; D014764:Viral Proteins / Q000378:metabolism*; D015678:Viral Structural Proteins / Q000378:metabolism
chemical_list: D010750:Phosphoproteins; C539757:V protein, Nipah virus; C069181:V protein, measles virus; D014764:Viral Proteins; D015678:Viral Structural Proteins; D054645:Protein Phosphatase 1; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1