Sequence-Specific Sensing of Nucleic Acids

Vabret, Nicolas; Bhardwaj, Nina; Greenbaum, Benjamin

doi:10.1016/j.it.2016.10.006

Cited by 47 publications

(48 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2H), see (Tanne et al 2015) and (Chatenay et al 2017) for an overview of the methods. Interestingly, in agreement with (Tanne et al 2015), satellite elements are the most diverse in terms of the CpG and UpA compositional bias, and consequently we proposed they are more likely to engage immune receptors such as pattern recognition receptors (PRRs) (Vabret et al 2017).…”

Section: Repetitive Elements Form Distinct Co-expression Clusterssupporting

confidence: 72%

Global Cancer Transcriptome Quantifies Repeat Element Polarization Between Immunotherapy Responsive and T cell Suppressive Classes

Solovyov

Vabret

Arora

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

SummaryGrowing evidence indicates that innate immune pathway activation is critical for responses to immunotherapy and overall cancer prognosis. It has been posited that innate immunity in the tumor microenvironment can be driven by derepression of endogenous repetitive element RNA. The ability to characterize these species can potentially provide novel predictive biomarkers for tumor immune responses and a mechanistic basis for elements of innate activation by tumors. We first compared total RNA and poly(A)-capture protocols applied to tumor RNA-sequencing to detect non-RNA coding transcriptomes in the TCGA. While the poly(A) protocol efficiently detects coding, most non-coding genes, and much of the LINE/SINE/ERV repeat repertoire, we found that it fails to capture overall repeat expression and co-expression. The probing of total RNA expression reveals distinct repetitive co-expression subgroups. Secondly, we found that total repeat element expression delivers the most dynamic changes in samples, which may serve as more robust biomarkers of clinical outcomes. Finally, we show that while expression of ERVs, but not other immunostimulatory repeats such as HSATII, is associated with response to immunotherapy in a cohort of patients with urothelial cancer treated with anti-PD-L1 therapy, global repeat derepression strongly correlates with an immunosuppressive phenotype in the microenvironment of colorectal and pancreatic tumors. We validate in situ in human primary tumors, associating the immunosuppressive phenotype with HSATII expression. In conclusion, we demonstrate the importance of analyzing repetitive element RNAs as potential biomarkers of response to immunotherapy and the need to better characterize these features in next generation sequencing protocols.

show abstract

Section: Repetitive Elements Form Distinct Co-expression Clusterssupporting

confidence: 72%

Global Cancer Transcriptome Quantifies Repeat Element Polarization Between Immunotherapy Responsive and T cell Suppressive Classes

Solovyov

Vabret

Arora

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is unclear how CpG dinucleotides restrict RNA virus replication but, for the picornavirus echovirus 7, it is not due to stimulating the interferon pathway, PKR, conventional pattern recognition receptors or altering the translation efficiency of viral proteins [71,74]. It has been hypothesized that there is an innate immune sensor that detects CpG dinucleotides in viral RNA and leads to the inhibition of viral replication, though the molecular details are unknown [71,73,74,85,92,[97][98][99]. We favor the hypothesis that the proposed active restriction pathway targeting CpG dinucleotides in RNA viruses inhibits HIV-1 with an increased CpG abundance.…”

Section: Discussionmentioning

confidence: 99%

Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication

et al. 2017

View full text Add to dashboard Cite

BackgroundThe human immunodeficiency virus type 1 (HIV-1) structural protein Gag is necessary and sufficient to form viral particles. In addition to encoding the amino acid sequence for Gag, the underlying RNA sequence could encode cis-acting elements or nucleotide biases that are necessary for viral replication. Furthermore, RNA sequences that inhibit viral replication could be suppressed in gag. However, the functional relevance of RNA elements and nucleotide biases that promote or repress HIV-1 replication remain poorly understood.ResultsTo characterize if the RNA sequence in gag controls HIV-1 replication, the matrix (MA) region was codon modified, allowing the RNA sequence to be altered without affecting the protein sequence. Codon modification of nucleotides (nt) 22-261 or 22-378 in gag inhibited viral replication by decreasing genomic RNA (gRNA) abundance, gRNA stability, Gag expression, virion production and infectivity. Comparing the effect of these point mutations to deletions of the same region revealed that the mutations inhibited infectious virus production while the deletions did not. This demonstrated that codon modification introduced inhibitory sequences. There is a much lower than expected frequency of CpG dinucleotides in HIV-1 and codon modification introduced a substantial increase in CpG abundance. To determine if they are necessary for inhibition of HIV-1 replication, codons introducing CpG dinucleotides were mutated back to the wild type codon, which restored efficient Gag expression and infectious virion production. To determine if they are sufficient to inhibit viral replication, CpG dinucleotides were inserted into gag in the absence of other changes. The increased CpG dinucleotide content decreased HIV-1 infectivity and viral replication.ConclusionsThe HIV-1 RNA sequence contains low abundance of CpG dinucleotides. Increasing the abundance of CpG dinucleotides inhibits multiple steps of the viral life cycle, providing a functional explanation for why CpG dinucleotides are suppressed in HIV-1.Electronic supplementary materialThe online version of this article (10.1186/s12977-017-0374-1) contains supplementary material, which is available to authorized users.

show abstract

“…Further confounding matters, we previously determined that conventional RNA sequencing approaches fail to capture the full spectrum of RNA expression in tumors ( 12 ). In particular, repetitive RNA, which can harbor immunostimulatory features ( 13 ), require further computational analysis for unbiased screening of their transcription. Here, we apply these approaches to identify novel RNA agonists of RIG-I-like receptors (RLRs).…”

Section: Mainmentioning

confidence: 99%

Y-RNAs Lead an Endogenous Program of RIG-I Agonism Mobilized upon RNA Virus Infection and Targeted by HIV

Vabret

Najburg

Solovyov

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

34Pattern recognition receptors (PRRs) protect against host invasion by detecting specific 35 molecular patterns found in pathogens and initiating an immune response. While 36 microbial-derived PRR ligands have been extensively characterized, the contribution and 37 relevance of endogenous ligands to PRR activation during viral infection remain 38 overlooked. In this work, we characterize the landscape of endogenous ligands that 39 engage RIG-I-like receptors (RLRs) upon infection by a positive-sense RNA virus, a 40 negative-sense RNA virus or a retrovirus. We found that several endogenous RNAs 41 transcribed by RNA polymerase 3 (Pol3) specifically engage RLRs, and in particular the 42 family of small non-coding repeats Y-RNAs, which presents the highest affinity as RIG-I 43 ligands. We show that this recognition is dependent on Y-RNA mimicking viral secondary 44 structure and its 5'-triphosphate extremity. Further, we found that HIV-1 infection triggers 45 a VPR-dependent downregulation of RNA triphosphatase DUSP11 in vitro and in vivo, 46 leading to an increase of Y-RNA 5'-triphosphorylation that enables their immunogenicity. 47Pattern Recognition Receptors (PRRs) were initially described as innate immune sensors 53 of molecular patterns commonly found in pathogens but rarely, if ever, found in their hosts. 54In recent years, this view has been challenged by evidence that ligands originating from 55 self can engage these same PRRs. Notably, sensing of self-RNA by innate receptors has 56 been observed in various settings such as autoimmune disorders (1-3), tumorigenesis 57 and cancer therapies (4-9) or infection by DNA viruses (10, 11). While the importance of 58 endogenous ligands in priming immune responses is progressively uncovered, little is 59 known about the breadth of biological processes in which they happen, nor about their 60 functional and evolutionary interplay with immune sensors. Furthermore, we lack 61 understanding of what features confers self-RNAs the ability to activate sensors and 62 whether this is a general response to aberrant transcription or is dominated by specific 63 RNA species. 64Further confounding matters, we previously determined that conventional RNA 65 sequencing approaches fail to capture the full spectrum of RNA expression in tumors (12). 66In particular, repetitive RNA, which can harbor immunostimulatory features (13), require 67 further computational analysis for unbiased screening of their transcription. Here, we 68 apply these approaches to identify novel RNA agonists of RIG-I-like receptors (RLRs). 69RLRs are a family of cytosolic RNA sensors composed of three members: RIG-I, LGP2 70 and MDA5 (14). Their intracellular localization and proximity with host RNA species 71 implies a delicate balance between a need to develop high affinity for microbial features 72 and the possibility to encounter self-RNAs that display similar structures. However, 73 despite a growing knowledge of the role of RLRs during RNA virus infection and the 74 microbial-derived ligands they recognize...

show abstract

Sequence-Specific Sensing of Nucleic Acids

Cited by 47 publications

References 96 publications

Global Cancer Transcriptome Quantifies Repeat Element Polarization Between Immunotherapy Responsive and T cell Suppressive Classes

Global Cancer Transcriptome Quantifies Repeat Element Polarization Between Immunotherapy Responsive and T cell Suppressive Classes

Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication

Y-RNAs Lead an Endogenous Program of RIG-I Agonism Mobilized upon RNA Virus Infection and Targeted by HIV

Contact Info

Product

Resources

About