Related Experiment Video
Updated: Jul 15, 2026
A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
Regulation of interferon production by RIG-I and LGP2: a lesson in self-control
Damien Vitour1, Eliane F Meurs
1Hepacivirus Unit, Pasteur Institute, Paris Cedex 15, France.
Abstract:
The cytoplasmic CARD-containing DExD/H box RNA helicases RIG-I and MDA5 act as sensors of viral infections through recognition of viral double-stranded (ds) RNAs. They both associate with the mitochondrial adaptor IPS-1 (also referred to as MAVS, VISA, and CARDIF) through homotypic CARD-CARD interactions. IPS-1, in turn, triggers signaling pathways, including activation of the protein kinases TBK1 and IKKepsilon, responsible for the phosphorylation of IRF3, a key transcription factor involved in interferon (IFN) synthesis, one essential element of the innate immune response. RIG-I remains in an autoinhibited state in the absence of dsRNA, through an internal repressor domain (RD) that binds within both its CARD and its RNA helicase domains and therefore acts in cis to control its multimerization and interaction with IPS-1. Ectopic expression of the RD prevents signaling and increases cell permissiveness to viruses, including hepatitis C virus. LGP2, which is another DExD/H RNA helicase of the RIG-I and MDA5 family and which is devoid of CARD domain, negatively controls IFN induction at different levels: by sequestering dsRNA, by blocking RIG-I's multimerization in trans through a domain analogous to the RIG-I RD, and by competing with the protein kinase IKKepsilon for a common interaction site on IPS-1. The ability of RIG-I and LGP2 to exert such a feedback control at the earliest steps of IFN synthesis allows the cells to exert a tight regulation of the induction of the innate immune response.
Insights
RIG-I and MDA5 sense viral RNA to initiate innate immunity. LGP2 negatively regulates this response, controlling interferon induction and maintaining immune balance.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Cytoplasmic RNA helicases RIG-I and MDA5 detect viral double-stranded RNA (dsRNA) to trigger innate immune responses.
- These sensors interact with the mitochondrial adaptor IPS-1, activating kinases like TBK1 and IKKepsilon, leading to IRF3 phosphorylation and interferon (IFN) synthesis.
- RIG-I is autoinhibited by its repressor domain (RD) in the absence of dsRNA, preventing self-multimerization and IPS-1 interaction.
Purpose of the Study:
- To elucidate the regulatory mechanisms of RIG-I-mediated innate immune signaling.
- To understand the role of LGP2, a CARD-less RNA helicase, in controlling IFN induction.
- To investigate how feedback control is exerted at the early stages of antiviral response.
Main Methods:
- Investigated the interaction between RIG-I, MDA5, IPS-1, and LGP2.
- Analyzed the function of the RIG-I repressor domain (RD) in regulating signaling.
- Studied the inhibitory mechanisms of LGP2 on RIG-I and downstream signaling pathways.
Main Results:
- RIG-I's RD binds intramolecularly to inhibit its CARD and helicase domains, controlling multimerization and IPS-1 interaction.
- Ectopic RD expression inhibits signaling and increases viral permissiveness.
- LGP2 negatively regulates IFN induction by sequestering dsRNA, inhibiting RIG-I multimerization, and competing with IKKepsilon for IPS-1 binding.
Conclusions:
- RIG-I and LGP2 play crucial roles in the innate immune response to viral infections.
- LGP2 acts as a negative feedback regulator, modulating RIG-I activity and downstream signaling.
- These regulatory mechanisms ensure tight control over the induction of the innate immune response, preventing excessive inflammation.
Related Concept Videos
01:30Inhibitors of Viral Protein Synthesis
01:31Regulation of the Unfolded Protein Response
01:23Regulation of Expression at Multiple Steps
02:24Regulation of Expression Occurs at Multiple Steps
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
02:24Regulation of Expression Occurs at Multiple Steps
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
01:23RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...