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

  • Nat Immunol. 2015 Oct;16(10):1025-33. doi: 10.1038/ni.3267.
Anna-Maria Herzner  1 ,  Cristina Amparo Hagmann  1 ,  Marion Goldeck  1 ,  Steven Wolter  1 ,  Kirsten Kübler  2 ,  Sabine Wittmann  3 ,  Thomas Gramberg  3 ,  Liudmila Andreeva  4 ,  Karl-Peter Hopfner  4 ,  Christina Mertens  1 ,  Thomas Zillinger  1  5 ,  Tengchuan Jin  6 ,  Tsan Sam Xiao  7 ,  Eva Bartok  1 ,  Christoph Coch  1 ,  Damian Ackermann  8 ,  Veit Hornung  9 ,  Janos Ludwig  1 ,  Winfried Barchet  1  5 ,  Gunther Hartmann  1 ,  Martin Schlee  1
Affiliations
  • 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.
PMID: 26343537 DOI: 10.1038/ni.3267
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.

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