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¹ Laboratory of Host Defense, World Premiere International Immunology Frontier Research Center, ² Research Institute for Microbial Diseases, ³ Institute for Scientific and Industrial Research, Osaka University, Suita, Osaka 565-0871, Japan
⁴ Department of Pharmacy, Hyogo University of Health Sciences, Cyuo-ku, Kobe, Hyogo 650-8530, Japan
⁵ Laboratory of Molecular Genetics, Institute for Virus Research, and ⁶ Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan
⁷ Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232

CORRESPONDENCE Shizuo Akira:sakira{at}biken.osaka-u.ac.jp

The ribonucleic acid (RNA) helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation–associated gene 5 (MDA5) recognize distinct viral and synthetic RNAs, leading to the production of interferons. Although 5'-triphosphate single-stranded RNA is a RIG-I ligand, the role of RIG-I and MDA5 in double-stranded (ds) RNA recognition remains to be characterized. In this study, we show that the length of dsRNA is important for differential recognition by RIG-I and MDA5. The MDA5 ligand, polyinosinic-polycytidylic acid, was converted to a RIG-I ligand after shortening of the dsRNA length. In addition, viral dsRNAs differentially activated RIG-I and MDA5, depending on their length. Vesicular stomatitis virus infection generated dsRNA, which is responsible for RIG-I–mediated recognition. Collectively, RIG-I detects dsRNAs without a 5'-triphosphate end, and RIG-I and MDA5 selectively recognize short and long dsRNAs, respectively.

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