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Nat Immunol. 2015 Oct;16(10):1025-33. doi: 10.1038/ni.3267. Epub 2015 Sep 7.

Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA.

Author information

1
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
2
Department of Obstetrics and Gynecology, Center for Integrated Oncology, University of Bonn, Bonn, Germany.
3
Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
4
Department Biochemistry, Gene Center, Ludwig-Maximilians University, Munich, Germany.
5
German Center of Infectious Disease, Cologne-Bonn, Germany.
6
School of Life Sciences, University of Science and Technology of China, Hefei, China.
7
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
8
LIMES Institute, Chemical Biology, University of Bonn, Bonn, Germany.
9
Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.

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.

PMID:
26343537
PMCID:
PMC4669199
DOI:
10.1038/ni.3267
[Indexed for MEDLINE]
Free PMC Article

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