Reconstitution of the RIG-I Pathway Reveals a Signaling Role of Unanchored Polyubiquitin Chains in Innate Immunity
| Autor: | Zhijian J. Chen, Anirban Adhikari, Ming ming Xu, Xiaomo Jiang, Wenwen Zeng, Lijun Sun, Xiang Chen, Fajian Hou |
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| Rok vydání: | 2010 |
| Předmět: |
TRIM25
Ubiquitin binding Ubiquitin-Protein Ligases viruses chemical and pharmacologic phenomena Biology Ubiquitin-conjugating enzyme Article General Biochemistry Genetics and Molecular Biology Cell Line DEAD-box RNA Helicases Tripartite Motif Proteins 03 medical and health sciences Adenosine Triphosphate 0302 clinical medicine Ubiquitin Polyphosphates Humans Receptors Immunologic MOLIMMUNO CELLCYLCE Polyubiquitin Transcription factor RNA Double-Stranded 030304 developmental biology 0303 health sciences RIG-I Biochemistry Genetics and Molecular Biology(all) virus diseases RNA biochemical phenomena metabolism and nutrition Molecular biology Immunity Innate I-kappa B Kinase 3. Good health Ubiquitin ligase Cell biology SIGNALING 030220 oncology & carcinogenesis Ubiquitin-Conjugating Enzymes biology.protein DEAD Box Protein 58 RNA Viral Interferon Regulatory Factor-3 biological phenomena cell phenomena and immunity Signal Transduction Transcription Factors |
| Zdroj: | Cell. 141(2):315-330 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2010.03.029 |
| Popis: | SummaryRIG-I detects invading viral RNA and activates the transcription factors NF-κB 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. |
| Databáze: | OpenAIRE |
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