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

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

Edité par CCSD ; Elsevier -

International audience. 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.

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