title: MDA5 detects the double-stranded RNA replicative form in picornavirus-infected cells.
abstract: RIG-I and MDA5 are cytosolic RNA sensors that play a critical role in innate antiviral responses. Major advances have been made in identifying RIG-I ligands, but our knowledge of the ligands for MDA5 remains restricted to data from transfection experiments mostly using poly(I:C), a synthetic dsRNA mimic. Here, we dissected the IFN-α/β-stimulatory activity of different viral RNA species produced during picornavirus infection, both by RNA transfection and in infected cells in which specific steps of viral RNA replication were inhibited. Our results show that the incoming genomic plus-strand RNA does not activate MDA5, but minus-strand RNA synthesis and production of the 7.5 kbp replicative form trigger a strong IFN-α/β response. IFN-α/β production does not rely on plus-strand RNA synthesis and thus generation of the partially double-stranded replicative intermediate. This study reports MDA5 activation by a natural RNA ligand under physiological conditions.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, PO Box 9101, 6500 HB, The Netherlands.
authors.forename: Qian
authors.initials: Q
authors.lastname: Feng
authors.forename: Stanleyson V
authors.initials: SV
authors.lastname: Hato
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Langereis
authors.forename: Jan
authors.initials: J
authors.lastname: Zoll
authors.forename: Richard
authors.initials: R
authors.lastname: Virgen-Slane
authors.forename: Alys
authors.initials: A
authors.lastname: Peisley
authors.forename: Sun
authors.initials: S
authors.lastname: Hur
authors.forename: Bert L
authors.initials: BL
authors.lastname: Semler
authors.forename: Ronald P
authors.initials: RP
authors.lastname: van Rij
authors.forename: Frank J M
authors.initials: FJ
authors.lastname: van Kuppeveld
mesh_terms: D000818:Animals; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006736:Horses; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010849:Picornaviridae / Q000235:genetics; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016898:Interferon-alpha; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D012367:RNA, Viral; D016899:Interferon-beta; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C