title: Measles virus suppresses RIG-I-like receptor activation in dendritic cells via DC-SIGN-mediated inhibition of PP1 phosphatases.
abstract: Dendritic cells (DCs) are targets of measles virus (MV) and play central roles in viral dissemination. However, DCs express the RIG-I-like receptors (RLRs) RIG-I and Mda5 that sense MV and induce type I interferon (IFN) production. Given the potency of this antiviral response, RLRs are tightly regulated at various steps, including dephosphorylation by PP1 phosphatases, which induces their activation. We demonstrate that MV suppresses RIG-I and Mda5 by activating the C-type lectin DC-SIGN and inducing signaling that prevents RLR dephosphorylation. MV binding to DC-SIGN leads to activation of the kinase Raf-1, which induces the association of PP1 inhibitor I-1 with GADD34-PP1 holoenzymes, thereby inhibiting phosphatase activity. Consequently, GADD34-PP1 holoenzymes are unable to dephosphorylate RIG-I and Mda5, hence suppressing type I IFN responses and enhancing MV replication. Blocking DC-SIGN signaling allows RLR activation and suppresses MV infection of DCs. Thus, MV subverts DC-SIGN to control RLR activation and escape antiviral responses.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 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, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Zijlstra-Willems
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Tanja M
authors.initials: TM
authors.lastname: Kaptein
authors.affiliation: Department of Virology, Erasmus MC, 's-Gravendijkwal 230, 3015 CA Rotterdam, the Netherlands.
authors.forename: Rik L
authors.initials: RL
authors.lastname: de Swart
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Davis
authors.affiliation: Department of Microbiology, Boston University, School of Medicine, Boston, MA 02118, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Ludlow
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.
authors.forename: Michaela U
authors.initials: MU
authors.lastname: Gack
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Electronic address: s.i.gringhuis@amc.uva.nl.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Gringhuis
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Electronic address: t.b.geijtenbeek@amc.uva.nl.
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
mesh_terms: D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D037181:Lectins, C-Type / Q000378:metabolism*; D008459:Measles virus / Q000276:immunology* / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D037181:Lectins, C-Type; D054645:Protein Phosphatase 1; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C452820:RIGI protein, human