MDA5 generates compact ribonucleoprotein complexes via ATP-dependent double-stranded RNA unwinding
Quack S, Maity S, America PP, Klein M, Herrero del Valle A, Singh R, Joiner JD, Rashid ZM, Smitskamp Q, Rivas P, Papini FS, Broedersz CP, Roos WH, Modis Y, Dulin D (2026)
Publication Type: Journal article
Publication year: 2026
Journal
Book Volume: 54
Journal Issue: 6
DOI: 10.1093/nar/gkag274
Abstract
Long double-stranded RNA (dsRNA) in the cytosol acts as a potent inflammatory molecule recognized by the receptor MDA5, triggering the innate immune response. Mutations affecting MDA5 ATPase activity lead to severe pathological conditions. MDA5 nucleoprotein filament assembly–disassembly dynamics are proposed to regulate dsRNA recognition, though the exact mechanism remains unclear. Here, we employed magnetic tweezers to monitor the assembly and manipulate MDA5 filaments at the single dsRNA level. Following a slow nucleation event, MDA5 assembles cooperatively and directionally into (partial) filaments and utilizes ATP hydrolysis to compact dsRNA through unwinding into single-stranded RNA (ssRNA), even against a significant opposing force. This compacted state is further stabilized by oligomerization of the caspase recruitment domain of MDA5 and requires high force to be disrupted. ssRNA gaps impaired compaction, suggesting a new mechanism for dsRNA recognition. We propose that MDA5-mediated dsRNA compaction captures viral dsRNA, preventing further usage for viral replication.
Involved external institutions
Vrije Universiteit Amsterdam (VU) / University Amsterdam
Netherlands (NL)
University of Groningen / Rijksuniversiteit Groningen
Netherlands (NL)
University of Cambridge
United Kingdom (GB)
Netherlands (NL)
University of Groningen / Rijksuniversiteit Groningen
Netherlands (NL)
University of Cambridge
United Kingdom (GB)
How to cite
APA:
Quack, S., Maity, S., America, P.P., Klein, M., Herrero del Valle, A., Singh, R.,... Dulin, D. (2026). MDA5 generates compact ribonucleoprotein complexes via ATP-dependent double-stranded RNA unwinding. Nucleic Acids Research, 54(6). https://doi.org/10.1093/nar/gkag274
MLA:
Quack, Salina, et al. "MDA5 generates compact ribonucleoprotein complexes via ATP-dependent double-stranded RNA unwinding." Nucleic Acids Research 54.6 (2026).
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