FAT10 inhibits TRIM21 to down-regulate antiviral type-I interferon secretion

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Type-I interferons (IFNs) are crucial for antiviral defense, with Influenza A virus infection stimulating their production.
• E3 ligase TRIM21 positively regulates type-I IFN production via a positive feedback loop.
• The ubiquitin-like modifier FAT10 negatively regulates type-I IFN responses and targets substrates for proteasomal degradation.

Purpose of the Study:

• To investigate the interaction between FAT10 and TRIM21.
• To elucidate the role of FAT10 in regulating TRIM21 stability and type-I IFN production during influenza A virus infection.

Main Methods:

• Investigated the covalent conjugation of FAT10 to TRIM21.
• Determined the domains of TRIM21 and FAT10 essential for their interaction.
• Assessed the impact of FAT10 on TRIM21 ubiquitination and proteasomal degradation.
• Measured IFNβ production in the context of FAT10-mediated TRIM21 degradation.

Main Results:

• FAT10 is covalently conjugated to TRIM21, targeting it for proteasomal degradation.
• The coiled-coil and PRYSPRY domains of TRIM21, and the C-terminal diglycine motif of FAT10, are critical for this interaction.
• FAT10-mediated degradation of TRIM21 reduces overall TRIM21 ubiquitination and diminishes IFNβ production during influenza A virus infection.

Conclusions:

• FAT10 down-regulates antiviral type-I IFN production by degrading TRIM21, a key regulator in the RIG-I signaling pathway.
• This study uncovers a novel mechanism by which FAT10 modulates TRIM21 stability and negatively impacts type-I IFN responses.
• FAT10 regulates additional molecules in the RIG-I signaling pathway beyond OTUB1, contributing to its role as a negative regulator of type-I IFN.