摘要：SummaryPattern 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 DUSP11in vitroandin 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.Graphical abstractDisplay OmittedHighlights•Y RNAs and other POL3 transcripts are RLRs ligands during RNA virus infections•Y RNA immunogenicity depends on their 5′-PPP and viral-mimicry secondary structure•Development of a novel sequencing approach to measure 5′-PPP status of RNA•HIV-1 VPR triggers DUSP11 downregulation and modulates host 5′-PPP transcriptomeBiological sciences; Immunology; Transcriptomics
