N6-Methyladenosine Modification Controls Circular RNA Immunity

Chen, Y. Grace; Chen, Robert; Ahmad, Sadeem; Verma, Rohit; Kasturi, Sudhir Pai; Amaya, Laura; Broughton, James P.; Kim, Jeewon; Cadena, Cristhian; Pulendran, Bali; Hur, Sun; Chang, Howard Y.

doi:10.1016/j.molcel.2019.07.016

Cited by 404 publications

(442 citation statements)

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“…additionally, activation of riG-i signalling by 5′-PPP rNa was shown to facilitate tumour responsiveness to checkpoint inhibitors 189,190 . Furthermore, in vitro synthesized circular RNAs have been proposed to activate RIG-I, and such RNA preparations induce antitumour responses in an in vivo model 191,192 . Circular rNas lack a 5′ end and whether riG-i activation is mediated directly by circular rNas or by other contaminating rNas is controversial 192,193 .…”

Section: Box 2 | Therapeutic Approaches and Synthetic Rlr Agonistsmentioning

confidence: 99%

“…Furthermore, in vitro synthesized circular RNAs have been proposed to activate RIG-I, and such RNA preparations induce antitumour responses in an in vivo model 191,192 . Circular rNas lack a 5′ end and whether riG-i activation is mediated directly by circular rNas or by other contaminating rNas is controversial 192,193 . Finally, stimulation of rLrs is of therapeutic use in vaccination models, which may be related to their role in modulating immune cell functions 186,[194][195][196][197] .…”

Section: Box 2 | Therapeutic Approaches and Synthetic Rlr Agonistsmentioning

confidence: 99%

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RIG-I-like receptors: their regulation and roles in RNA sensing

2020

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| Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are key sensors of virus infection, mediating the transcriptional induction of type I interferons and other genes that collectively establish an antiviral host response. Recent studies have revealed that both viral and host-derived RNAs can trigger RLR activation; this can lead to an effective antiviral response but also immunopathology if RLR activities are uncontrolled. In this Review , we discuss recent advances in our understanding of the types of RNA sensed by RLRs in the contexts of viral infection, malignancies and autoimmune diseases. We further describe how the activity of RLRs is controlled by host regulatory mechanisms, including RLR-interacting proteins, post-translational modifications and non-coding RNAs. Finally , we discuss key outstanding questions in the RLR field, including how our knowledge of RLR biology could be translated into new therapeutics.

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Section: Box 2 | Therapeutic Approaches and Synthetic Rlr Agonistsmentioning

confidence: 99%

Section: Box 2 | Therapeutic Approaches and Synthetic Rlr Agonistsmentioning

confidence: 99%

RIG-I-like receptors: their regulation and roles in RNA sensing

2020

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“…It is also conceivable that circRNAs set epigenetic marks on viral or host cell genes, making circRNA abundances to perform specific functions less relevant. Finally, N 6 -methyladenosine modification in circRNAs has been shown to impact innate immune responses [56–58]. Thus, differential modification of circRNAs that are up-regulated or down-regulated during viral infections may systemically deliver innate sensors to uninfected bystander cells.…”

Section: Discussionmentioning

confidence: 99%

Host-derived Circular RNAs Display Proviral Activities in Hepatitis C Virus - Infected Cells

Chen

Talló-Parra

Kadener

et al. 2020

Preprint

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2930 Viruses subvert macromolecular pathways in infected host cells to aid in viral gene amplification 31 or to counteract innate immune responses. Roles for host-encoded RNAs, including 32 microRNAs, have been found to provide pro-and anti-viral functions. Recently, circular RNAs 33 (circRNAs), that are generated by a nuclear back-splicing mechanism of pre-mRNAs, have 34 been implicated to have roles in DNA virus-infected cells. This study examines the circular RNA 35 landscape in uninfected and hepatitis C virus (HCV)-infected liver cells. Results showed that the 36 abundances of distinct classes of circRNAs were up-regulated or down-regulated in infected 37 cells. Identified circRNAs displayed pro-viral effects. One particular up-regulated circRNA, 38 circPSD3, displayed a very pronounced effect on viral RNA abundances in both hepatitis C 39 virus-and Dengue virus-infected cells. Surprisingly, circPSD3 also inhibited the cellular 40 nonsense-mediated decay (NMD) pathway in liver cells. Thus, enhanced abundance of 41 circPSD3 in virus-infected cells aids in viral replication and likely contributes to the known 42 inhibition of NMD in HCV-infected cells. Findings from the global analyses of the circular RNA 43 landscape argue pro-, and likely, anti-viral functions are executed by circRNAs that modulate 44 both viral gene expression as well as host pathways. Because of their long half-lives, circRNAs 45 likely play hitherto unknown, important roles in viral pathogenesis. 46 47 48 Author Summary 49 50 Usually, cells are infected by one or a few virus particles that carry genomes with limited 51 expression capacity. Thus, the expression of viral genomes has to compete with a sea of 52 cellular components that aid in viral translation, replication and virion production. Depending on 53 their lifestyle, viruses have evolved to avoid or to subvert cellular pathways, especially those 3 54 that display anti-viral functions. Host-derived circular RNA molecules have recently been 55 discovered in the cytoplasm of cells, although, as-of yet, few functions have been assigned to 56 them. Here, we describe alterations in the circular RNA landscape in hepatitis C virus-infected 57 liver cells. Up-regulated and down-regulated circular RNAs were identified, and three of the 58 upregulated RNAs were shown to promote HCV infection. One of them, circPSD3, inhibited the 59 cellular nonsense-mediated RNA decay that is a powerful antiviral response in infected cells. 60 Because circular RNAs are more stable than linear RNAs, they may have important functions 61 during viral infection, dictating the outcomes of innate immune responses and viral 62 pathogenesis. 63 64 Introduction 65 66 Cicrular RNAs (circRNAs) were first detected in plant viral RNA pathogens, termed viroids [1].67 Subsequently, it has shown that eukaryotic cells express circRNAs as well [2, 3]. Some 68 circRNAs contain scrambled exons, which are produced by an abnormal splicing mechanism 69 [4]. Recently, it has been shown that circRNA species are synthesized from pre-...

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“…As early as 2017, Howard Y. Chang reported that cells can recognize intracellular circRNA (endogenous circRNA) and in vitro synthesized circRNA (exogenous circRNA) by retinoic acid-inducible gene I (RIG-I), which can activate the autoimmune pathway (40). Then, they further proved that circFOREIGEN or PEI packaging circFOREIGEN both can play a similar role to poly(I: C) in vivo, and found that cells can distinguish between endogenous circRNAs and exogenous circRNAs by identifying whether carried N6-Methyladenosine modification (m6A modifications) (41). They further concluded that exogenous circRNAs without m6A modification bind to K63-linked ubiquitin chains (K63-Ubn) and RIG-I and promote RIG-I polymerization and activation, thereby promoting the polymerization of downstream mitochondrial antiviral signal (MAVS) and inducing the dimerization activation of Interferon Regulating Factor 3 (IRF3), and ultimately inducing the expression of genes in the autoimmune pathway.…”

Section: Circrnas In Immune Regulationmentioning

confidence: 99%

The Role of Circular RNAs in Immune-Related Diseases

Xie

Zhang

et al. 2020

Front. Immunol.

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Circular RNAs (circRNAs) are a novel class of RNAs with a covalently closed loop structure without a 3 ′ polyadenylation [poly-(A)] tail or a 5 ′ cap. They used to be considered as the occasional and useless products of RNA splicing errors because they could not be detected by traditional RNA sequencing technology. Benefiting from the development of specific biochemical and computational approaches, researchers showed that circRNAs are universally expressed and functional. Further studies have revealed their important functions regarding regulating gene expression at the transcriptional and post-transcriptional levels. These functions include acting as microRNA (miRNA) sponges, binding to RNA-binding proteins (RBPs), acting as transcriptional regulatory factors, and serving as translation templates. The advances in circRNA research has opened researchers' eyes to a new area of research on the roles of circRNAs in the pathogenesis of various diseases, especially at the immune level because of the close relationship between circRNAs and the immune response. Emerging research indicates that circRNAs could act as potential biomarkers related to diagnosis, therapeutic effects, and prognosis, and they may be effective therapeutic targets in immunological disorders, including certain diseases that are currently difficult to treat.

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N6-Methyladenosine Modification Controls Circular RNA Immunity

Cited by 404 publications

References 47 publications

RIG-I-like receptors: their regulation and roles in RNA sensing

RIG-I-like receptors: their regulation and roles in RNA sensing

Host-derived Circular RNAs Display Proviral Activities in Hepatitis C Virus - Infected Cells

The Role of Circular RNAs in Immune-Related Diseases

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