RIG-I–like Receptor Regulation of Immune Cell Function and Therapeutic Implications

Abstract

Retinoic acid–inducible gene I–like receptors (RLRs) are cytosolic RNA sensors critical for initiation of antiviral immunity. Activation of RLRs following RNA recognition leads to production of antiviral genes and IFNs for induction of broad antiviral immunity. Although the RLRs are ubiquitously expressed, much of our understanding of these molecules comes from their study in epithelial cells and fibroblasts. However, RLR activation is critical for induction of immune function and long-term protective immunity. Recent work has focused on the roles of RLRs in immune cells and their contribution to programming of effective immune responses. This new understanding of RLR function in immune cells and immune programming has led to the development of vaccines and therapeutics targeting the RLRs. This review covers recent advances in our understanding of the contribution of RLRs to immune cell function during infection and the emerging RLR-targeting strategies for induction of immunity against cancer and viral infection.

Filoviruses: Innate Immunity, Inflammatory Cell Death, and Cytokines

“…Most human cell types express RLRs in the cytosol, though some RLRs have been visualized in the nucleus [66]. Three human RLRs have been identified to date: RIG-I, melanoma differentiation-associated factor 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) [67]. Though some structural differences exist, RIG-I and MDA5 contain two N-terminal caspase activation and recruitment domains (CARDs), two DExD/H box RNA helicase domains, and a C-terminal domain (CTD); by contrast, LGP2 lacks a CARD [68][69][70].…”

Interaction of SARS-CoV-2 Nucleocapsid Protein and Human RNA Helicases DDX1 and DDX3X Modulates Their Activities on Double-Stranded RNA

“…RIG-I binding of dsRNA leads to the activation of the IPS-1 (MAV) adaptor protein located on the outer mitochondrial membrane. This in turn mobilizes the kinase complex TBK1/IKKe, phosphorylating the transcription factor IRF3 which leads to IFN-b production [ 36 ]. DDX3X has been shown to be an essential component of this pathway.…”

Recent developments in understanding RIG-I's activation and oligomerization

“…Multiple pathogen-sensing pathways can trigger the induction of interferons, which is important not only for antiviral immunity but also for the induction of antitumor immunity. 38 On the other hand, the dysregulation of RIG-I signaling can lead to a wide variety of autoimmune diseases. 38 , 39 In this section, we will cover only emerging RIG-I related diseases and new strategies harnessing the RIG-I pathway in autoimmune diseases and in induction of the immunity against viral infections.…”