Skip to content
DraconiticResearch
Search Sources API
203,203 studies31 sourcesUpdated 19 min ago
Peer-reviewedCC BYNucleic acids research

Establishing the molecular basis for MDA5 mutation-linked autoimmunity.

  • Ling Xu1,2,3
  • Harim Jang1,2
  • Kevin Chung4
  • Rong Guo5
  • Alisia Pan1
  • Anna Marie Pyle1,2
5 affiliations
  1. 1Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, United States.
  2. 2Howard Hughes Medical Institute, Chevy Chase, MD 20815, United States.
  3. 3Department of Chemistry, The Wertheim UF Scripps Institute, Jupiter, FL 33458, United States.
  4. 4Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, United States.
  5. 5Department of Chemistry, Yale University, New Haven, CT 06511, United States.
Read full textPDFDOICite

Abstract

Melanoma differentiation-associated protein 5 (MDA5), a member of the RIG-I-like receptor family, is a cytoplasmic sensor essential for innate antiviral immunity. MDA5 distinguishes viral RNA from host RNA in part through its ATP hydrolysis activity, which promotes filament turnover on shorter endogenous double-stranded RNAs (dsRNAs). Here, we show that the gain-of-function T331I disease-linked mutation within the ATP-binding pocket disrupts this balance, resulting in constitutive interferon signaling. Through a combination of cryo-electron microscopy (cryoEM), biochemical assays, and cellular analyses, we reveal the extensive network of interactions that precisely position ATP for catalysis in the wild-type MDA5 ATP-binding pocket and also demonstrate that the T331I mutation impairs ATPase activity, thereby stabilizing MDA5-dsRNA complexes and leading to aberrant immune activation. These findings elucidate how MDA5 ATPase activity regulates antiviral specificity and prevents autoimmunity by controlling filament stability and downstream signaling, offering a mechanistic molecular explanation for disease pathogenesis.

Related

  1. X-linked hyper IgM syndrome with a novel CD40-ligand gene mutation suffered from infection of Talaromyces marneffei
    Juan Gu, Aiyan Ren, Jing Kong +6
    Frontiers in immunologyPeer-reviewedCC BYFull textImmunologyEurope PMC
  2. ALS-linked FUS mutation impairs GEMIN5-dependent mRNA recruitment to neuronal late endosomes
    Adriano Setti, Lorenzo Stufera Mecarelli, Tiziana Santini +7
    Cell ReportsPeer-reviewedCC BY-NC 4.0Full textGeneral biologyCrossrefDOAJ
  3. A mutation-agnostic and allele-specific ASO strategy demonstrates potent functional rescue and retinal preservation in RHO-linked retinitis pigmentosa
    S. Spaag, W.-H. Wu, J. Yun +28
    bioRxivPreprintCC BY-NC-NDFull textGenetics & genomicsbioRxiv
  4. A novel CD40LG frameshift mutation in an Iranian family with X-linked hyper-IgM syndrome: A case report
    Fatemeh Farzi, Mohammad Panahi, Ebrahim Sakhinia +1
    Molecular Genetics and Metabolism ReportsPeer-reviewedCC BY 4.0Full textImmunologyPMCEurope PMC
  5. Establishing an ex vivo platform for molecular profiling of skin structural cells using frozen human skin biopsies
    A. Takamori, H. DeBerg, P. Morawski +5
    bioRxivPreprintCC BY-NC-NDFull textImmunologybioRxiv

Cite

BibTeXRIS
BibTeX
@article{xu2026establishing,
  title = {{Establishing the molecular basis for MDA5 mutation-linked autoimmunity.}},
  author = {Ling Xu and Harim Jang and Kevin Chung and Rong Guo and Alisia Pan and Anna Marie Pyle},
  journal = {Nucleic acids research},
  year = {2026},
  month = sep,
  doi = {10.1093/nar/gkag941},
  url = {https://europepmc.org/article/MED/42847245},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Establishing the molecular basis for MDA5 mutation-linked autoimmunity.
AU  - Ling Xu
AU  - Harim Jang
AU  - Kevin Chung
AU  - Rong Guo
AU  - Alisia Pan
AU  - Anna Marie Pyle
PY  - 2026
DA  - 2026/09/01
JO  - Nucleic acids research
DO  - 10.1093/nar/gkag941
UR  - https://europepmc.org/article/MED/42847245
AB  - Melanoma differentiation-associated protein 5 (MDA5), a member of the RIG-I-like receptor family, is a cytoplasmic sensor essential for innate antiviral immunity. MDA5 distinguishes viral RNA from host RNA in part through its ATP hydrolysis activity, which promotes filament turnover on shorter endogenous double-stranded RNAs (dsRNAs). Here, we show that the gain-of-function T331I disease-linked mutation within the ATP-binding pocket disrupts this balance, resulting in constitutive interferon signaling. Through a combination of cryo-electron microscopy (cryoEM), biochemical assays, and cellular analyses, we reveal the extensive network of interactions that precisely position ATP for catalysis in the wild-type MDA5 ATP-binding pocket and also demonstrate that the T331I mutation impairs ATPase activity, thereby stabilizing MDA5-dsRNA complexes and leading to aberrant immune activation. These findings elucidate how MDA5 ATPase activity regulates antiviral specificity and prevents autoimmunity by controlling filament stability and downstream signaling, offering a mechanistic molecular explanation for disease pathogenesis.
SN  - 0305-1048
SN  - 1362-4962
ER  -