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MDA5 generates compact ribonucleoprotein complexes via ATP-dependent double-stranded RNA unwinding
Salina Quack1,2, Sourav Maity3, Pim P B America1
1Department of Physics and Astronomy, and LaserLaB Amsterdam, Vrije Universiteit Amsterdam, De Boelelaan 1100, 1081 HZ Amsterdam, The Netherlands.
Nucleic Acids Research
|March 31, 2026
Summary
MDA5 receptor uses ATP hydrolysis to unwind long dsRNA into ssRNA, forming filaments that capture viral RNA and prevent replication. This mechanism is crucial for innate immunity and preventing disease.
Area of Science:
- Molecular Biology
- Immunology
- Biophysics
Background:
- Long double-stranded RNA (dsRNA) in the cytosol is recognized by MDA5, initiating the innate immune response.
- Dysfunctional MDA5 ATPase activity is linked to severe pathological conditions.
- MDA5 filament dynamics are implicated in dsRNA recognition, but the precise mechanism is unknown.
Purpose of the Study:
- To investigate the mechanism of MDA5 filament assembly and dsRNA compaction at the single-molecule level.
- To elucidate the role of ATP hydrolysis in MDA5-mediated dsRNA recognition.
Main Methods:
- Utilized magnetic tweezers to monitor and manipulate single MDA5-dsRNA filaments.
- Analyzed MDA5 filament assembly, dsRNA compaction, and the effect of ATP hydrolysis.
Main Results:
- Observed cooperative, directional MDA5 filament assembly on dsRNA.
- Demonstrated that MDA5 uses ATP hydrolysis to compact dsRNA into ssRNA against significant force.
- Showed that ssRNA gaps impede compaction, suggesting a novel recognition mechanism.
- Found that the compacted state is stabilized by MDA5 CARD oligomerization and requires high force to disrupt.
Conclusions:
- MDA5 actively compacts dsRNA into ssRNA via ATP-dependent unwinding.
- This compaction mechanism, influenced by ssRNA gaps, represents a new mode of dsRNA recognition.
- MDA5-mediated dsRNA compaction likely serves to sequester viral RNA, inhibiting viral replication and contributing to innate immunity.
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