Phase separation in innate immunity: Teleost IL6Ra's evolutionary leap against viruses

Area of Science:

• Immunology
• Evolutionary Biology
• Biochemistry

Background:

• Phase separation is an emerging regulatory mechanism in innate immunity.
• Interleukin-6 receptor alpha (IL6Ra) in teleost fish possesses a unique intrinsically disordered region (IDR).

Purpose of the Study:

• To investigate the role of the unique IDR in teleost IL6Ra in innate immunity and viral defense.
• To elucidate the mechanism by which IL6Ra-mediated phase separation enhances antiviral responses.

Main Methods:

• Comparative sequence analysis of IL6Ra across vertebrates.
• In vitro and in vivo studies on zebrafish IL6Ra's phase separation properties.
• Assessment of antiviral activity with and without the IDR region.

Main Results:

• Teleost IL6Ra's IDR enables liquid-liquid phase separation (LLPS), distinct from higher vertebrates.
• IL6Ra-mediated LLPS competitively recruits G3bp1, inhibiting viral replication and activating antiviral pathways.
• The IDR's characteristics and length correlate positively with phase separation ability and antiviral capacity.
• IL6Ra lacking the IDR shows significantly weakened antiviral capability.

Conclusions:

• The IDR of IL6Ra provides an evolutionary strategy for rapid innate immune response in teleost fish.
• Environmental pressures have driven divergence in IDR sequences, optimizing LLPS-dependent antiviral defense.
• Protein disordered regions play a critical role in adaptive evolution and immune system diversification.