Journal Article

The 3' untranslated regions of influenza genomic sequences are 5'PPP-independent ligands for RIG-I

Sambhara, Suryaprakash, Katz, Jacqueline M, Gangappa, Shivaprakash, Donis, Ruben O, Bowzard, J Bradford, Sharma, Suresh D, Ranjan, Priya, Davis, William G, Stuchlik, Olga, Pohl, Jan, Fujita, Takashi, Cameron, Craig E, Wiens, Mayim E

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 3' Untranslated Regions / 5' Untranslated Regions / Binding Sites - genetics / Biological response modifiers / Cell Line / DEAD Box Protein 58 / DEAD-box RNA Helicases - chemistry / DEAD-box RNA Helicases - metabolism / Genome, Viral / Host-Pathogen Interactions - genetics / Host-Pathogen Interactions - immunology / Host-Pathogen Interactions - physiology / Humans / Influenza / Influenza A virus - genetics / Influenza A virus - immunology / Influenza A virus - metabolism / Interferon / Interferon-beta - biosynthesis / Interferon-beta - genetics / Kinetics / Ligands / Nucleic Acid Conformation / Public-private sector cooperation / Receptors, Immunologic / RNA / RNA, Viral - chemistry / RNA, Viral - genetics / RNA, Viral - metabolism / Viral Nonstructural Proteins - genetics