Regulation of RIG-I-like receptor-mediated signaling: interaction between host and viral factors

Cell Mol Immunol. 2021 Mar;18(3):539-555. doi: 10.1038/s41423-020-00602-7. Epub 2021 Jan 18.


Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are RNA sensor molecules that play essential roles in innate antiviral immunity. Among the three RLRs encoded by the human genome, RIG-I and melanoma differentiation-associated gene 5, which contain N-terminal caspase recruitment domains, are activated upon the detection of viral RNAs in the cytoplasm of virus-infected cells. Activated RLRs induce downstream signaling via their interactions with mitochondrial antiviral signaling proteins and activate the production of type I and III interferons and inflammatory cytokines. Recent studies have shown that RLR-mediated signaling is regulated by interactions with endogenous RNAs and host proteins, such as those involved in stress responses and posttranslational modifications. Since RLR-mediated cytokine production is also involved in the regulation of acquired immunity, the deregulation of RLR-mediated signaling is associated with autoimmune and autoinflammatory disorders. Moreover, RLR-mediated signaling might be involved in the aberrant cytokine production observed in coronavirus disease 2019. Since the discovery of RLRs in 2004, significant progress has been made in understanding the mechanisms underlying the activation and regulation of RLR-mediated signaling pathways. Here, we review the recent advances in the understanding of regulated RNA recognition and signal activation by RLRs, focusing on the interactions between various host and viral factors.

Keywords: Innate immunity; RIG-I-like receptors; Stress response; Viral infection.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • DEAD Box Protein 58 / immunology*
  • Humans
  • Immunologic Factors
  • Interferon Lambda
  • Interferon Type I / immunology
  • Interferons / immunology
  • Mitochondria / immunology*
  • Receptors, Immunologic / immunology*
  • Signal Transduction*
  • Virus Diseases / immunology*
  • Viruses / immunology*


  • Immunologic Factors
  • Interferon Type I
  • Receptors, Immunologic
  • Interferons
  • DDX58 protein, human
  • DEAD Box Protein 58
  • Interferon Lambda