ArticleNature communications2021
MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- A Fish MDA5 Integrates Canonical RIG-I and MDA5 Ligand Recognition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Establishing the molecular basis for MDA5 mutation-linked autoimmunity.Nucleic acids research · 2026Article
- Distinguishing self from non-self RNA by editing-specific inosine patterns.Nucleic acids research · 2026Article
- LINE-1 Epigenetic Repression and Regulation of Immunity.Viruses · 2026Review
- Structural and mechanistic basis of ADAR1-mediated RNA editing and immune regulation.Cell insight · 2026Review
- MDA5 generates compact ribonucleoprotein complexes via ATP-dependent double-stranded RNA unwinding.Nucleic acids research · 2026Article
- ATP-dependent one-dimensional movement maintains immune homeostasis by suppressing spontaneous MDA5 filament assembly.Cell research · 2025Article
- Molecular basis of autoimmune disease protection by MDA5 variants.Cell reports · 2025Article
- MDA5 variants trade antiviral activity for protection from autoimmune disease.BMC medical genomics · 2025Article
- The Type 1 Diabetes-Associated Single Nucleotide Polymorphism rs1990760 in IFIH1 Is Associated with Increased Basal Type I IFNs and IFN-stimulated Gene Expression.Journal of immunology (Baltimore, Md. : 1950) · 2024Article
- Multifaceted roles of RNA editing enzyme ADAR1 in innate immunity.RNA (New York, N.Y.) · 2024Article
- MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance.JCI insight · 2023Article
- Activation of cytosolic RNA sensors by endogenous ligands: roles in disease pathogenesis.Frontiers in immunology · 2023Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 3 countries.
Funding
Abstract
Our innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. Mutations that reduce RNA selectivity can cause autoinflammatory disease. Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition. M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA. M854K MDA5 lacks ATPase activity and binds more stably to synthetic Alu:Alu dsRNA. CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 sidechain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle- RNA footprint expansion and helical twist modulation. The M854K mutation inhibits ATP-dependent RNA proofreading via an allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs. This work provides insights on how MDA5 recognizes dsRNA in health and disease.
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