ATP-dependent effector-like functions of RIG-I like receptors

• Published in: Molecular cell 2015-05, Vol.58 (3), p.541-548
• Main Authors: Yao, Hui, Dittmann, Meike, Peisley, Alys, Hoffmann, Hans-Heinrich, Gilmore, Rachel H., Schmidt, Tobias, Schmidt-Burgk, Jonathan, Hornung, Veit, Rice, Charles M., Hur, Sun
• Format: Article
• Language: English
• Subjects: adenosine triphosphate; Adenosine Triphosphate - metabolism; Antiviral Agents - metabolism; Base Sequence; Blotting, Western; Cell Line, Tumor; DEAD Box Protein 58; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; double-stranded RNA; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; HEK293 Cells; Humans; hydrolysis; innate immunity; Interferon-beta - genetics; Interferon-beta - metabolism; Interferon-Induced Helicase, IFIH1; interferons; Models, Molecular; Mutation; Nucleic Acid Conformation; Phosphorylation; receptors; Receptors, Immunologic; Receptors, Pattern Recognition - genetics; Receptors, Pattern Recognition - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Double-Stranded - chemistry; RNA, Double-Stranded - genetics; RNA, Double-Stranded - metabolism; RNA, Viral - chemistry; RNA, Viral - genetics; RNA, Viral - metabolism; vertebrates; viral proteins; Viral Proteins - genetics; Viral Proteins - metabolism; Virus Diseases - genetics; Virus Diseases - metabolism; virus replication; viruses
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2015.03.014

The vertebrate antiviral innate immune system is often considered to consist of two distinct groups of proteins: pattern recognition receptors (PRRs) that detect viral infection and induce the interferon (IFN) signaling, and effectors that directly act against viral replication. Accordingly, previous studies on PRRs, such as RIG-I and MDA5, have primarily focused on their functions in viral double-stranded RNA (dsRNA) detection and consequent antiviral signaling. We here report that both RIG-I and MDA5 efficiently displace viral proteins pre-bound to dsRNA in a manner dependent on their ATP hydrolysis, and that this activity assists a dsRNA-dependent antiviral effector protein, PKR, and allows RIG-I to promote MDA5 signaling. Furthermore, truncated RIG-I/MDA5 lacking the signaling domain, and hence the IFN stimulatory activity, displace viral proteins and suppress replication of certain viruses in an ATP-dependent manner. Thus, this study reveals novel “effector-like” functions of RIG-I and MDA5 that challenge the conventional view of PRRs. •RIG-I and MDA5 displace viral proteins bound to dsRNA in an ATP-dependent manner.•2CARD deletion mutants, RIG-IΔN and MDA5ΔN, relieve the viral suppression of PKR.•RIG-IΔN relieves the viral suppression of the MDA5 signaling activity.•RIG-IΔN/MDA5ΔN suppress replication of certain viruses in an ATP-dependent manner.