Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid–inducible gene-I and melanoma differentiation–associated gene 5

TLDR

RIG‑I and MDA5 are RNA helicases that recognize distinct viral and synthetic RNAs to induce interferons, but their roles in double‑stranded RNA recognition remain unclear. In this study, we show that the length of dsRNA is important for differential recognition by RIG‑I and MDA5. Shortening dsRNA converts the MDA5 ligand poly I:C into a RIG‑I ligand, and viral dsRNAs activate RIG‑I or MDA5 depending on length, with VSV‑derived dsRNA triggering RIG‑I; overall, RIG‑I detects short dsRNAs lacking a 5′‑triphosphate while MDA5 preferentially recognizes long dsRNAs.

Abstract

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.