1. Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA
- Author
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Cristina Amparo Hagmann, Janos Ludwig, Tsan Sam Xiao, Thomas Gramberg, Veit Hornung, Damian Ackermann, Sabine Wittmann, Marion Goldeck, Thomas Zillinger, Liudmila Andreeva, Martin Schlee, Anna-Maria Herzner, Christoph Coch, Kirsten Kübler, Karl-Peter Hopfner, Tengchuan Jin, Winfried Barchet, Eva Bartok, Steven Wolter, Christina Mertens, and Gunther Hartmann
- Subjects
DNA, Complementary ,Base pair ,Immunology ,Alpha interferon ,Cell Line ,chemistry.chemical_compound ,Mice ,Retrovirus ,Interferon ,Complementary DNA ,medicine ,Immunology and Allergy ,Animals ,Humans ,Nucleotide ,Cells, Cultured ,chemistry.chemical_classification ,biology ,Interferon-alpha ,DNA virus ,biology.organism_classification ,Virology ,Molecular biology ,Nucleotidyltransferases ,HEK293 Cells ,chemistry ,DNA, Viral ,HIV-1 ,Immunization ,DNA ,medicine.drug - Abstract
Cytosolic DNA that emerges during infection with a retrovirus or DNA virus triggers antiviral type I interferon responses. So far, only double-stranded DNA (dsDNA) over 40 base pairs (bp) in length has been considered immunostimulatory. Here we found that unpaired DNA nucleotides flanking short base-paired DNA stretches, as in stem-loop structures of single-stranded DNA (ssDNA) derived from human immunodeficiency virus type 1 (HIV-1), activated the type I interferon-inducing DNA sensor cGAS in a sequence-dependent manner. DNA structures containing unpaired guanosines flanking short (12- to 20-bp) dsDNA (Y-form DNA) were highly stimulatory and specifically enhanced the enzymatic activity of cGAS. Furthermore, we found that primary HIV-1 reverse transcripts represented the predominant viral cytosolic DNA species during early infection of macrophages and that these ssDNAs were highly immunostimulatory. Collectively, our study identifies unpaired guanosines in Y-form DNA as a highly active, minimal cGAS recognition motif that enables detection of HIV-1 ssDNA.
- Published
- 2014