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

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

Authors

  • Zeng W
  • Sun L
  • Jiang X
  • Chen X
  • Hou F
  • Adhikari A
  • Xu M
  • Chen ZJ

Journal

Cell

Publication Data

April 16, 2010

Associated Grants

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

Mesh Terms

  • Adenosine Triphosphate
  • Cell Line
  • 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
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases