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Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity
- Source :
- Nature, 505(7485), 691, Nature
- Publication Year :
- 2014
-
Abstract
- The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.
- Subjects :
- viruses
Biology
Virus
Article
Substrate Specificity
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Interferon
medicine
Animals
Cluster Analysis
RNA Viruses
Gene
Virus classification
030304 developmental biology
Gene Library
Genetics
Mice, Knockout
0303 health sciences
Multidisciplinary
Cyclic GMP-AMP synthase
DNA Viruses
RNA
Membrane Proteins
RNA virus
biology.organism_classification
Flow Cytometry
Virology
Nucleotidyltransferases
Immunity, Innate
3. Good health
STAT1 Transcription Factor
chemistry
030220 oncology & carcinogenesis
Viruses
Interferon Regulatory Factor-3
Interferons
DNA
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Nature, 505(7485), 691, Nature
- Accession number :
- edsair.doi.dedup.....32754cfae90b975a9347d0c03cc83c78