RNA Helicase LGP2 Negatively Regulates RIG-I Signaling by Preventing TRIM25-Mediated Caspase Activation and...

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are crucial for detecting viral RNA and initiating antiviral immunity.
• LGP2 (also known as DHX58) is an RLR that modulates RIG-I signaling, but its precise regulatory mechanism remains unclear.

Purpose of the Study:

• To elucidate the role of LGP2 in RIG-I signaling and myeloid cell antiviral responses.
• To investigate how LGP2 deficiency impacts the transcriptional profile and immune activation.

Main Methods:

• Utilized a RIG-I agonist to stimulate wild-type and Dhx58 knockout bone marrow-derived dendritic cells.
• Analyzed transcriptional profiles to compare responses between cell types.
• Performed mutational analysis of LGP2 and mass spectrometry to identify interacting proteins.
• Assessed TRIM25-mediated ubiquitination of RIG-I.

Main Results:

• Dhx58 knockout cells showed significantly enhanced and accelerated type I interferon (IFN) induction and a broader antiviral response.
• LGP2 was found to inhibit RIG-I-mediated IFN-β, IRF-3, and NF-κB promoter activities.
• RNA binding, ATP hydrolysis, and the C-terminal domain of LGP2 were not essential for its inhibitory function.
• LGP2 directly interacts with the E3 ubiquitin ligase TRIM25.
• LGP2 inhibits TRIM25-dependent K63-specific ubiquitination of the RIG-I N-terminus, which is critical for signaling.

Conclusions:

• LGP2 acts as a negative regulator of RIG-I-mediated antiviral signaling.
• LGP2's inhibitory function is mediated through its interaction with TRIM25, preventing RIG-I ubiquitination and subsequent activation.
• Understanding LGP2's role provides insights into fine-tuning innate immune responses against viral infections.