PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1

  • Cell. 2015 Jun 4;161(6):1293-1305. doi: 10.1016/j.cell.2015.04.050.
Sunnie M Yoh  1 ,  Monika Schneider  1 ,  Janna Seifried  #  2 ,  Stephen Soonthornvacharin  #  1 ,  Rana E Akleh  1 ,  Kevin C Olivieri  1 ,  Paul D De Jesus  1 ,  Chunhai Ruan  3 ,  Elisa de Castro  4 ,  Pedro A Ruiz  1 ,  David Germanaud  5 ,  Vincent des Portes  6 ,  Adolfo García-Sastre  4  7 ,  Renate König  2  1  8 ,  Sumit K Chanda  1
Affiliations
  • 1. Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.
  • 2. Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, D-63225 Langen, Germany.
  • 3. Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor, MI 48109.
  • 4. Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029.
  • 5. APHP, Hôpital Robert Debré, DHU PROTECT, Service de Neurologie Pédiatrique et Pathologie Métabolique, F-75019 Paris 2. Sorbonne Paris Cité, Université Paris Diderot, F-75010.
  • 6. National Reference Center for Fragile X and Other XLID, Biobank NeuroBioTec, Hospices Civils de Lyon, Université de Lyon and CNRS UMR 5304 (L2C2), Bron, France.
  • 7. Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029.
  • 8. German Center for Infection Research (DZIF), Langen, Germany.
  • # Contributed equally.
PMID: 26046437 DOI: 10.1016/j.cell.2015.04.050
Abstract

Dendritic cells (DCs) play a critical role in the immune response to viral Infection through the facilitation of cell-intrinsic Antiviral activity and the activation of adaptive immunity. HIV-1 Infection of DCs triggers an IRF3-dependent innate immune response, which requires the activity of cyclic GAMP synthase (cGAS). We report the results of a targeted RNAi screen utilizing primary human monocyte-derived DCs (MDDCs) to identify immune regulators that directly interface with HIV-1-encoded features to initiate this innate response. Polyglutamine binding protein 1 (PQBP1) emerged as a strong candidate through this analysis. We found that PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate response. MDDCs derived from Renpenning syndrome patients, who harbor mutations in the PQBP1 locus, possess a severely attenuated innate immune response to HIV-1 challenge, underscoring the role of PQBP1 as a proximal innate sensor of a HIV-1 Infection.