Abstract

RIG-I-like receptors (RLRs: RIG-I, MDA5 and LGP2) play a major role in the innate immune response against viral infections and detect patterns on viral RNA molecules that are typically absent from host RNA. Upon RNA binding, RLRs trigger a complex downstream signaling cascade resulting in the expression of type I interferons and proinflammatory cytokines. In the past decade extensive efforts were made to elucidate the nature of putative RLR ligands. In vitro and transfection studies identified 5′-triphosphate containing blunt-ended double-strand RNAs as potent RIG-I inducers and these findings were confirmed by next-generation sequencing of RIG-I associated RNAs from virus-infected cells. The nature of RNA ligands of MDA5 is less clear. Several studies suggest that double-stranded RNAs are the preferred agonists for the protein. However, the exact nature of physiological MDA5 ligands from virus-infected cells needs to be elucidated. In this work, we combine a crosslinking technique with next-generation sequencing in order to shed light on MDA5-associated RNAs from human cells infected with measles virus. Our findings suggest that RIG-I and MDA5 associate with AU-rich RNA species originating from the mRNA of the measles virus L gene. Corresponding sequences are poorer activators of ATP-hydrolysis by MDA5 in vitro, suggesting that they result in more stable MDA5 filaments. These data provide a possible model of how AU-rich sequences could activate type I interferon signaling.

Highlights

  • The retinoic acid inducible gene I (RIG-I)-like receptor (RLR) proteins are key players in innate immunity and act by recognizing viral RNA in the cytosol

  • The RIG-I-like receptors (RLRs) family consists of the members retinoic acid inducible gene I (RIG-I), melanoma differentiation associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) [1,2,3]

  • In vitro studies have shown that RIG-I and MDA5 recognize the majority of viruses in a complementary manner

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Summary

Introduction

The retinoic acid inducible gene I (RIG-I)-like receptor (RLR) proteins are key players in innate immunity and act by recognizing viral RNA (vRNA) in the cytosol. The RLR family consists of the members retinoic acid inducible gene I (RIG-I), melanoma differentiation associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) [1,2,3]. In vitro studies have shown that RIG-I and MDA5 recognize the majority of viruses in a complementary manner. While many negative-strand RNA viruses like rabies and influenza viruses are predominantly sensed by RIG-I, picornaviruses are predominantly recognized by MDA5. In case of MDA5, a minor contribution to recognition of measles, rabies, vesicular stomatitis and Sendai virus has been reported [10,11,12,13]

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