title: PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1.
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.
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.
authors.forename: Sunnie M
authors.initials: SM
authors.lastname: Yoh
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.
authors.forename: Monika
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, D-63225 Langen, Germany.
authors.forename: Janna
authors.initials: J
authors.lastname: Seifried
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.
authors.forename: Stephen
authors.initials: S
authors.lastname: Soonthornvacharin
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.
authors.forename: Rana E
authors.initials: RE
authors.lastname: Akleh
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Olivieri
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.
authors.forename: Paul D
authors.initials: PD
authors.lastname: De Jesus
authors.affiliation: Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor, MI 48109.
authors.forename: Chunhai
authors.initials: C
authors.lastname: Ruan
authors.affiliation: Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Castro
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Ruiz
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Germanaud
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.affiliation: Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029.|Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, D-63225 Langen, Germany.|Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.|German Center for Infection Research (DZIF), Langen, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: König
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92116.
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Chanda
mesh_terms: D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002547:Cerebral Palsy / Q000276:immunology; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D038901:X-Linked Intellectual Disability / Q000276:immunology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D002352:Carrier Proteins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009713:Nucleotidyltransferases; C119246:PQBP1 protein, human; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase