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

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

doi:10.1016/j.isci.2022.104599

Cited by 18 publications

(16 citation statements)

References 63 publications

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“…A growing body of literature documents the role of RIG-I-like receptor (RLR)-mediated sensing of endogenous ligands in autoimmune diseases and cancer (8,37). Similar to RNA5SP141, the host-derived RLR ligands found in these disease contexts are typically noncoding RNAs, however, from different subclasses (38)(39)(40). RNA mislocalization, changes in the stoichiometry of RNA versus RNA-binding proteins, and impairment of specific RNA-modifying enzymes (e.g., DUSP11 and ADAR1) have been found to underlie aberrant RLR activation (38,(40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141

et al. 2022

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Herpes simplex virus 1 (HSV-1) infects several billion people worldwide and can cause life-threatening herpes simplex encephalitis (HSE) in some patients. Monogenic defects in components of the type I interferon system have been identified in patients with HSE, emphasizing the role of inborn errors of immunity underlying HSE pathogenesis. Here, we identify compound heterozygous loss-of-function mutations in the gene GTF3A encoding for transcription factor IIIA (TFIIIA), a component of the RNA polymerase III complex, in a patient with common variable immunodeficiency and HSE. Patient fibroblasts and GTF3A gene–edited cells displayed impaired HSV-1–induced innate immune responses and enhanced HSV-1 replication. Chromatin immunoprecipitation sequencing analysis identified the 5 S ribosomal RNA pseudogene 141 ( RNA5SP141 ), an endogenous ligand of the RNA sensor RIG-I, as a transcriptional target of TFIIIA. GTF3A mutant cells exhibited diminished RNA5SP141 expression and abrogated RIG-I activation upon HSV-1 infection. Our work unveils a crucial role for TFIIIA in transcriptional regulation of a cellular RIG-I agonist and shows that GTF3A genetic defects lead to impaired cell-intrinsic anti–HSV-1 responses and can predispose to HSE.

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Section: Discussionmentioning

confidence: 99%

GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141

et al. 2022

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“…IFN-α is a cytokine associated with viral infection, including by SARS-CoV-2 [Galbraith et al, 2022]; therefore, increased Y-RNA levels may be triggered by IFN-α that is released during infection. Interestingly, Y-RNA is triphosphorylated and can thereby trigger cellular RNA sensors such as RIG-I, leading to IFN-α production [Hornung et al, 2006; Vabret et al, 2022]. We hypothesize that Y-RNA may play a role in a feed-forward loop driving antiviral cytokine expression during SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

Viral and host small RNA transcriptome analysis of SARS-CoV-1 and SARS-CoV-2-infected human cells reveals novel viral short RNAs

Nyberg

Conte

Sültmann

et al. 2022

Preprint

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RNA viruses have been shown to express various short RNAs, some of which have regulatory roles during replication, transcription, and translation of viral genomes. However, short viral RNAs (svRNAs) generated by SARS-CoV-1 and SARS-CoV-2 remained largely unexplored, mainly due limitations of the widely used library preparation methods for small RNA deep sequencing and corresponding data processing. By analyzing publicly available small RNA-seq datasets, we observed that human cells infected by SARS-CoV-1 or SARS-CoV-2 produce multiple short viral RNAs (svRNAs), ranging in size from 15 to 26 nt and deriving predominantly from (+) RNA strands. In addition, we verified the presence of the five most abundant SARS-CoV-2 svRNAs in SARS-CoV-2-infected human lung adenocarcinoma cells by qPCR. Interestingly, the copy number of the observed SARS-CoV-2 svRNAs dramatically exceeded the expression of previously reported viral miRNAs in the same cells. We hypothesize that the reported SARS-CoV-2 svRNAs could serve as biomarkers for early infection stages due to their high abundance. Finally, we found that both SARS-CoV-1 and SARS-CoV-2 infection induced up- and down-regulation of multiple endogenous human short RNAs that align predominantly to protein-coding and lncRNA transcripts. Interestingly, a significant proportion of short RNAs derived from full-length viral genomes also aligned to various hg38 sequences, suggesting opportunities to investigate regulatory roles of svRNAs during infection. Further characterization of the small RNA landscape of both viral and host genomes is clearly warranted to improve our understanding of molecular events related to infection and to design more efficient strategies for therapeutic interventions as well as early diagnosis.

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“…In addition, A to I editing of endogenous dsRNA by adenosine deaminase acting on RNA 1 (ADAR1) can prevent sensing of self-RNA by MDA5 and triggering MAVSmediated type I interferon response [35,37,38]. Nevertheless, RLRs can sense endogenous RNA and even DNA that are mislocalized or misprocessed in cells [33,[39][40][41][42]. The endogenous noncoding RNAs associated with RIG-I include small nucleolar RNA (snRNA), signal recognition particle RNA (srpRNA), transfer RNA (tRNA), vault RNA, Y RNA and retrotransposon-derived RNAs [33,40,41].…”

Section: An Overview Of Rlrs Signalingmentioning

confidence: 99%

“…Nevertheless, RLRs can sense endogenous RNA and even DNA that are mislocalized or misprocessed in cells [33,[39][40][41][42]. The endogenous noncoding RNAs associated with RIG-I include small nucleolar RNA (snRNA), signal recognition particle RNA (srpRNA), transfer RNA (tRNA), vault RNA, Y RNA and retrotransposon-derived RNAs [33,40,41]. In addition, the accumulation of mitochondrial dsRNA species in the cytoplasm may induce interferon response through the MDA5-MAVS axis, especially when the mitochondrial dsRNA is cleaved by RNAase L [42,43].…”

Section: An Overview Of Rlrs Signalingmentioning

confidence: 99%

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

et al. 2023

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RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize “immune-cold” tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy.

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

Cited by 18 publications

References 63 publications

GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141

GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141

Viral and host small RNA transcriptome analysis of SARS-CoV-1 and SARS-CoV-2-infected human cells reveals novel viral short RNAs

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

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