MAVS deSUMOylation by SENP1 inhibits its aggregation and antagonizes IRF3 activation

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Mitochondrial antiviral signaling protein (MAVS) is essential for innate antiviral immunity.
• MAVS acts as an adapter to recruit and activate Interferon Regulatory Factor 3 (IRF3).
• The precise molecular mechanisms governing MAVS and IRF3 interactions remain largely unelucidated.

Purpose of the Study:

• To investigate the role of SUMOylation in regulating MAVS function and antiviral immunity.
• To identify the mechanisms by which MAVS recruits and activates IRF3.
• To explore the interplay between MAVS post-translational modifications and its phase separation properties.

Main Methods:

• Western blotting to detect SUMOylation and ubiquitination.
• Immunofluorescence microscopy to visualize protein aggregation and droplet formation.
• Co-immunoprecipitation assays to study protein-protein interactions.
• Site-directed mutagenesis to investigate the role of SUMO-interacting motifs (SIMs).

Main Results:

• SUMO-specific protease 1 negatively regulates antiviral immunity by deSUMOylating MAVS.
• Virus infection induces PIAS3-mediated poly-SUMOylation of MAVS, promoting its aggregation and K63-linked poly-ubiquitination.
• SUMOylation facilitates MAVS phase separation into droplets via a novel SIM in MAVS.
• A newly identified SIM in IRF3 mediates its recruitment to MAVS droplets.
• IRF3 phosphorylation near its SIM disrupts SUMO-SIM interactions, releasing activated IRF3.

Conclusions:

• SUMOylation is a critical regulator of MAVS phase separation and antiviral immune signaling.
• The SUMOylation-dependent recruitment and release mechanism of IRF3 from MAVS droplets provides a novel regulatory pathway for antiviral responses.
• This study reveals a previously unknown mechanism controlling the timely activation of innate antiviral immunity.