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Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity.

Cell | Apr 16, 2010

RIG-I detects invading viral RNA and activates the transcription factors NF-kappaB and IRF3 through the mitochondrial protein MAVS. Here we show that RNA bearing 5'-triphosphate strongly activates the RIG-I-IRF3 signaling cascade in a reconstituted system composed of RIG-I, mitochondria, and cytosol. Activation of RIG-I requires not only RNA but also polyubiquitin chains linked through lysine 63 (K63) of ubiquitin. RIG-I binds specifically to K63-polyubiquitin chains through its tandem CARD domains in a manner that depends on RNA and ATP. Mutations in the CARD domains that abrogate ubiquitin binding also impair RIG-I activation. Remarkably, unanchored K63-ubiquitin chains, which are not conjugated to any target protein, potently activate RIG-I. These ubiquitin chains function as an endogenous ligand of RIG-I in human cells. Our results delineate the mechanism of RIG-I activation, identify CARD domains as a ubiquitin sensor, and demonstrate that unanchored K63-polyubiquitin chains are signaling molecules in antiviral innate immunity.

Pubmed ID: 20403326 RIS Download

Mesh terms: Adenosine Triphosphate | Cell Line | DEAD Box Protein 58 | DEAD-box RNA Helicases | Humans | I-kappa B Kinase | Immunity, Innate | Interferon Regulatory Factor-3 | Polyphosphates | Polyubiquitin | RNA, Double-Stranded | RNA, Viral | Signal Transduction | Transcription Factors | Tripartite Motif Proteins | Ubiquitin-Conjugating Enzymes | Ubiquitin-Protein Ligases

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Associated grants

  • Agency: NIGMS NIH HHS, Id: R01-GM63692
  • Agency: NIAID NIH HHS, Id: F32 AI009919
  • Agency: NIAID NIH HHS, Id: R01-AI09919
  • Agency: NIGMS NIH HHS, Id: R01 GM063692-08
  • Agency: NIGMS NIH HHS, Id: R01 GM063692
  • Agency: Howard Hughes Medical Institute, Id:

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