Y RNAs are conserved endogenous RIG-I ligands across RNA virus infection and are targeted by HIV-1

Nicolas Vabret; Valérie Najburg; Alexander Solovyov; Ramya Gopal; Christopher McClain; Petr Šulc; Sreekumar Balan; Yannis Rahou; Guillaume Beauclair; Maxime Chazal; Hugo Varet; Rachel Legendre; Odile Sismeiro; Raul Y Sanchez David; Lise Chauveau; Nolwenn Jouvenet; Martin Markowitz; Sylvie van der Werf; Olivier Schwartz; Frédéric Tangy; Nina Bhardwaj; Benjamin D Greenbaum; Anastassia V Komarova

doi:10.1016/j.isci.2022.104599

Y RNAs are conserved endogenous RIG-I ligands across RNA virus infection and are targeted by HIV-1

iScience. 2022 Jun 11;25(7):104599. doi: 10.1016/j.isci.2022.104599. eCollection 2022 Jul 15.

Authors

Nicolas Vabret^{1

2

3}, Valérie Najburg⁴, Alexander Solovyov⁵, Ramya Gopal^{1

2

3}, Christopher McClain^{1

2

3}, Petr Šulc⁶, Sreekumar Balan^{1

2

3}, Yannis Rahou⁷, Guillaume Beauclair⁴, Maxime Chazal⁴, Hugo Varet^{8

9}, Rachel Legendre^{8

9}, Odile Sismeiro⁸, Raul Y Sanchez David⁴, Lise Chauveau¹⁰, Nolwenn Jouvenet⁴, Martin Markowitz¹¹, Sylvie van der Werf⁷, Olivier Schwartz¹⁰, Frédéric Tangy⁴, Nina Bhardwaj^{1

2

3

12}, Benjamin D Greenbaum^{5

13}, Anastassia V Komarova^{4

7}

Affiliations

¹ Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³ Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁴ Viral Genomics and Vaccination Unit, Department of Virology, Institut Pasteur, Université de Paris, CNRS UMR-3569, 75015 Paris, France.
⁵ Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁶ Center for Molecular Design and Biomimetics at the Biodesign Institute and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA.
⁷ Molecular Genetics of RNA Viruses, Department of Virology, Institut Pasteur, Université de Paris, CNRS UMR-3569, 75015 Paris, France.
⁸ Transcriptome and EpiGenome Platform, BioMics, Center of Innovation and Technological Research, Institut Pasteur, Université de Paris, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France.
⁹ Hub Informatique et Biostatistique, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI, USR 3756 IP-CNRS), Institut Pasteur, Université de Paris, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France.
¹⁰ Virus & Immunity Unit, Department of Virology, Institut Pasteur, Université de Paris, CNRS UMR-3569, 75015 Paris, France.
¹¹ Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY, USA.
¹² Extra-mural Member, Parker Institute of Cancer Immunotherapy, USA.
¹³ Physiology, Biophysics, & Systems Biology, Weill Cornell Medicine, New York, NY 10065, USA.

Abstract

Pattern recognition receptors (PRRs) protect against microbial invasion by detecting specific molecular patterns found in pathogens and initiating an immune response. Although microbial-derived PRR ligands have been extensively characterized, the contribution and relevance of endogenous ligands to PRR activation remains overlooked. Here, we characterize the landscape of endogenous ligands that engage RIG-I-like receptors (RLRs) upon infection by different RNA viruses. In each infection, several RNAs transcribed by RNA polymerase III (Pol3) specifically engaged RLRs, particularly the family of Y RNAs. Sensing of Y RNAs was dependent on their mimicking of viral secondary structure and their 5'-triphosphate extremity. Further, we found that HIV-1 triggered a VPR-dependent downregulation of RNA triphosphatase DUSP11 in vitro and in vivo, inducing a transcriptome-wide change of cellular RNA 5'-triphosphorylation that licenses Y RNA immunogenicity. Overall, our work uncovers the contribution of endogenous RNAs to antiviral immunity and demonstrates the importance of this pathway in HIV-1 infection.

Keywords: Biological sciences; Immunology; Transcriptomics.

Abstract

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