Histone demethylase LSD1 promotes RIG-I poly-ubiquitination and anti-viral gene expression

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Retinoic acid-inducible gene I (RIG-I) is crucial for detecting viral RNA and initiating antiviral responses.
• Protein methyltransferases and demethylases are implicated in cellular signaling pathways.
• The specific role of these enzymes in RIG-I-mediated antiviral immunity requires elucidation.

Purpose of the Study:

• To identify protein methyltransferases and demethylases involved in the RIG-I antiviral signaling pathway.
• To characterize the function and mechanism of identified regulators in antiviral immunity.

Main Methods:

• Screening of known protein methyltransferases and demethylases using a siRNA library.
• Assessing RIG-I signaling activation upon viral stimulation.
• Investigating protein-protein interactions using co-immunoprecipitation.
• Evaluating the impact of LSD1 on RIG-I ubiquitination and downstream signaling.
• In vivo validation of LSD1's role in antiviral gene expression and viral replication.

Main Results:

• Lysine-specific demethylase 1 (LSD1) was identified as a positive regulator of RIG-I signaling.
• LSD1 enhances RIG-I signaling, while its deficiency impairs antiviral responses.
• LSD1 interacts with RIG-I, promoting its K63-linked polyubiquitination and association with VISA/MAVS.
• LSD1's function is independent of its demethylase activity, relying instead on enhancing RIG-I interactions with E3 ligases like TRIM25.
• In vivo studies confirmed that LSD1 boosts antiviral gene expression and inhibits viral replication.

Conclusions:

• LSD1 acts as a positive regulator in the RIG-I-mediated antiviral signaling pathway.
• LSD1 facilitates RIG-I polyubiquitination, enhancing antiviral immunity against RNA viruses.
• LSD1's role in antiviral response is mediated through its interaction with E3 ligases, independent of its enzymatic demethylase activity.