MDA5 assembles into a polar helical filament on dsRNA

Area of Science:

• Immunology
• Structural Biology
• Virology

Background:

• Melanoma differentiation-associated protein 5 (MDA5) is a key sensor of viral double-stranded RNA (dsRNA) in the cytoplasm.
• MDA5 activation leads to the assembly of the mitochondrial antiviral-signaling protein (MAVS) into active signaling fibrils.
• The precise molecular mechanism governing MDA5-mediated signaling remains incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanism of MDA5 signaling upon viral dsRNA binding.
• To determine the 3D structure of MDA5 filaments formed on dsRNA.

Main Methods:

• Electron microscopy (EM) and image reconstruction were employed to determine the 3D structure of MDA5 filaments.
• Homology modeling was used to fit the MDA5 protein structure into the reconstructed filament.

Main Results:

• MDA5 forms polar, single-start helical filaments around dsRNA.
• The C-terminal domain of MDA5 appears crucial for cooperative filament assembly.
• The helical array of MDA5 nucleates the assembly of MAVS fibrils, supporting a signal transduction model.

Conclusions:

• MDA5 functions as a polymerization-dependent signaling platform.
• The helical filament formation of MDA5 is essential for initiating antiviral signaling.
• MDA5 leverages the amyloid-like properties of MAVS for signal amplification.