title: The 3' untranslated regions of influenza genomic sequences are 5'PPP-independent ligands for RIG-I.
abstract: Retinoic acid inducible gene-I (RIG-I) is a key regulator of antiviral immunity. RIG-I is generally thought to be activated by ssRNA species containing a 5'-triphosphate (PPP) group or by unphosphorylated dsRNA up to ~300 bp in length. However, it is not yet clear how changes in the length, nucleotide sequence, secondary structure, and 5' end modification affect the abilities of these ligands to bind and activate RIG-I. To further investigate these parameters in the context of naturally occurring ligands, we examined RNA sequences derived from the 5' and 3' untranslated regions (UTR) of the influenza virus NS1 gene segment. As expected, RIG-I-dependent interferon-β (IFN-β) induction by sequences from the 5' UTR of the influenza cRNA or its complement (26 nt in length) required the presence of a 5'PPP group. In contrast, activation of RIG-I by the 3' UTR cRNA sequence or its complement (172 nt) exhibited only a partial 5'PPP-dependence, as capping the 5' end or treatment with CIP showed a modest reduction in RIG-I activation. Furthermore, induction of IFN-β by a smaller, U/A-rich region within the 3' UTR was completely 5'PPP-independent. Our findings demonstrated that RNA sequence, length, and secondary structure all contributed to whether or not the 5'PPP moiety is needed for interferon induction by RIG-I.
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: William G
authors.initials: WG
authors.lastname: Davis
authors.forename: J Bradford
authors.initials: JB
authors.lastname: Bowzard
authors.forename: Suresh D
authors.initials: SD
authors.lastname: Sharma
authors.forename: Mayim E
authors.initials: ME
authors.lastname: Wiens
authors.forename: Priya
authors.initials: P
authors.lastname: Ranjan
authors.forename: Shivaprakash
authors.initials: S
authors.lastname: Gangappa
authors.forename: Olga
authors.initials: O
authors.lastname: Stuchlik
authors.forename: Jan
authors.initials: J
authors.lastname: Pohl
authors.forename: Ruben O
authors.initials: RO
authors.lastname: Donis
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Katz
authors.forename: Craig E
authors.initials: CE
authors.lastname: Cameron
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.forename: Suryaprakash
authors.initials: S
authors.lastname: Sambhara
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000378:metabolism*; D016679:Genome, Viral; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology / Q000502:physiology; D006801:Humans; D009980:Influenza A virus / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics; D007700:Kinetics; D008024:Ligands; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011971:Receptors, Immunologic; D017361:Viral Nonstructural Proteins / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; C551867:5'PPP-RNA; C085820:INS1 protein, influenza virus; D008024:Ligands; D012367:RNA, Viral; D011971:Receptors, Immunologic; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases