Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses

Tang, Qingli; Rigby, Rachel E.; Young, George R.; Hvidt, Astrid Korning; Davis, Tanja; Tan, Tiong Kit; Bridgeman, Anne; Townsend, Alain; Kassiotis, George; Rehwinkel, Jan

doi:10.1016/j.immuni.2021.08.011

Cited by 84 publications

(98 citation statements)

References 105 publications

(163 reference statements)

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“…To elucidate the biological significance of Z-RNA-binding to ADAR1 p150 in vivo, various studies, analyzing mutant mice harboring single or double point mutation(s) in Zα, have been reported [ 77 , 78 , 79 , 80 , 81 ]. Adar1 knock-in (KI) mice that harbor a P195A point mutation, corresponding to human AGS-causative P193A mutation ( Figure 2 ), show no overt phenotypes [ 80 , 81 ].…”

Section: Preventing Z-rna Binding Of Adar1 P150 Induces Ags-like Encephalopathymentioning

confidence: 99%

“…These findings suggest that the P193A mutation most likely affects the RNA-editing activity of ADAR1 p150 to some extent but not enough to induce phenotypic abnormalities, which might explain the reason why homozygous point mutations in Zα have not been identified in patients with AGS to date. In contrast, Adar1 KI mice harboring N175A/Y179A point mutations exhibit increased expression of ISGs in multiple organs, which lasts more than a year [ 78 , 79 ]. N175A/Y179A point mutations correspond to an N173A/Y177A substitution in human ADAR1 p150, both of which reduce Z-DNA-binding capacity in vitro [ 76 ] ( Figure 2 and Figure 4 ).…”

Section: Preventing Z-rna Binding Of Adar1 P150 Induces Ags-like Encephalopathymentioning

confidence: 99%

“…N175A/Y179A point mutations correspond to an N173A/Y177A substitution in human ADAR1 p150, both of which reduce Z-DNA-binding capacity in vitro [ 76 ] ( Figure 2 and Figure 4 ). However, although only male Adar1 N175A:Y179A/N175A:Y179A mice are leaner, these mutant mice survive beyond a year without displaying specific abnormalities in certain organs, suggesting chronically enhanced expression of ISGs is not sufficient to induce abnormal pathology [ 78 , 79 ]. Notably, Adar1 N175A:Y179A/− mice cannot survive beyond postnatal day 1, which is more deleterious than found for Adar1 P195A/− mice [ 78 , 80 ].…”

Section: Preventing Z-rna Binding Of Adar1 P150 Induces Ags-like Encephalopathymentioning

confidence: 99%

“…In Adar1 N175A:Y179A/N175A:Y179A and Adar1 W197A/W197A mice, the expression of ADAR1 p150, which is an ISG, is increased, leading to enhanced RNA editing at a subset of, but not all, target sites [ 77 , 79 ]. In addition, ADAR1 p110 and ADAR2 are normally expressed, which makes it difficult to understand the pattern of RNA editing in Zα-mutated Adar1 KI mice.…”

Section: Preventing Z-rna Binding Of Adar1 P150 Induces Ags-like Encephalopathymentioning

confidence: 99%

“…However, the phenotypes of Adar1 W197A/E861A mice are more deleterious than those of Adar1 W197A/W197A mice [ 77 ]. These findings suggest that reduced RNA editing at certain sites, which cannot be ameliorated by increased expression of mutant ADAR1 p150, causes aberrant activation of the MDA5-sensing pathway in these Zα-mutated Adar1 KI mice [ 77 , 78 , 79 ] ( Figure 5 ). Indeed, we found that some sites in the 3′UTR of Rnf168 and 2900026A02Rik show reduced RNA editing and do not respond to increased expression of ADAR1 p150 (W197A) in the brains of Adar1 W197A/W197A mice [ 77 ].…”

Section: Preventing Z-rna Binding Of Adar1 P150 Induces Ags-like Encephalopathymentioning

confidence: 99%

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Deciphering the Biological Significance of ADAR1–Z-RNA Interactions

Nakahama

Kawahara

2021

IJMS

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Adenosine deaminase acting on RNA 1 (ADAR1) is an enzyme responsible for double-stranded RNA (dsRNA)-specific adenosine-to-inosine RNA editing, which is estimated to occur at over 100 million sites in humans. ADAR1 is composed of two isoforms transcribed from different promoters: p150 and N-terminal truncated p110. Deletion of ADAR1 p150 in mice activates melanoma differentiation-associated protein 5 (MDA5)-sensing pathway, which recognizes endogenous unedited RNA as non-self. In contrast, we have recently demonstrated that ADAR1 p110-mediated RNA editing does not contribute to this function, implying that a unique Z-DNA/RNA-binding domain α (Zα) in the N terminus of ADAR1 p150 provides specific RNA editing, which is critical for preventing MDA5 activation. In addition, a mutation in the Zα domain is identified in patients with Aicardi–Goutières syndrome (AGS), an inherited encephalopathy characterized by overproduction of type I interferon. Accordingly, we and other groups have recently demonstrated that Adar1 Zα-mutated mice show MDA5-dependent type I interferon responses. Furthermore, one such mutant mouse carrying a W197A point mutation in the Zα domain, which inhibits Z-RNA binding, manifests AGS-like encephalopathy. These findings collectively suggest that Z-RNA binding by ADAR1 p150 is essential for proper RNA editing at certain sites, preventing aberrant MDA5 activation.

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Section: Preventing Z-rna Binding Of Adar1 P150 Induces Ags-like Encephalopathymentioning

confidence: 99%

Section: Preventing Z-rna Binding Of Adar1 P150 Induces Ags-like Encephalopathymentioning

confidence: 99%

Section: Preventing Z-rna Binding Of Adar1 P150 Induces Ags-like Encephalopathymentioning

confidence: 99%

Section: Preventing Z-rna Binding Of Adar1 P150 Induces Ags-like Encephalopathymentioning

confidence: 99%

Section: Preventing Z-rna Binding Of Adar1 P150 Induces Ags-like Encephalopathymentioning

confidence: 99%

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Deciphering the Biological Significance of ADAR1–Z-RNA Interactions

Nakahama

Kawahara

2021

IJMS

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Z‐nucleic acids: Uncovering the functions from past to present

Tang

2022

Eur J Immunol

Self Cite

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Since Z-nucleic acid was identified in the 1970s, much is still unknown about its biological functions and nature in vivo. Recent studies on adenosine deaminase acting on RNA 1 (ADAR1) and Z-DNA-binding protein 1 (ZBP1) have highlighted its function in immune responses. Specifically, Z-RNAs, either endogenous or induced by viral infection, are sensed by ZBP1 and activate necroptosis. Z-RNAs act as the stimuli that induce innate immune responses through various pathways, including melanoma differentiationassociated protein 5 (MAD5)-mitochondrial antiviral-signaling protein (MAVS)-mediated type I IFN activation and proteinase kinase R (PKR)-dependent integrated stress response, and their immunostimulatory potential is curtailed by RNA editing conducted by ADAR1. Aberrant immune responses induced by Z-RNAs are associated with human diseases. They also induce pathogenesis in mice. Unlike Z-RNAs, the biological functions of Z-DNAs were barely studied, especially in mammals. Moreover, the origin or sequence preference of Z-nucleic acids requires further investigation. Such knowledge will expand our understanding of Z-nucleic acids, including from which genomic loci and under which circumstances they form, and the mechanisms by which they participate in the physiological activities. In this review, we provide insights in Z-nucleic acid research and highlight the unsolved puzzles.

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A‐to‐I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy

Datta,

Adamska,

Bhate

et al. 2023

WIREs RNA

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ADAR deaminases catalyze adenosine‐to‐inosine (A‐to‐I) editing on double‐stranded RNA (dsRNA) substrates that regulate an umbrella of biological processes. One of the two catalytically active ADAR enzymes, ADAR1, plays a major role in innate immune responses by suppression of RNA sensing pathways which are orchestrated through the ADAR1‐dsRNA‐MDA5 axis. Unedited immunogenic dsRNA substrates are potent ligands for the cellular sensor MDA5. Upon activation, MDA5 leads to the induction of interferons and expression of hundreds of interferon‐stimulated genes with potent antiviral activity. In this way, ADAR1 acts as a gatekeeper of the RNA sensing pathway by striking a fine balance between innate antiviral responses and prevention of autoimmunity. Reduced editing of immunogenic dsRNA by ADAR1 is strongly linked to the development of common autoimmune and inflammatory diseases. In viral infections, ADAR1 exhibits both antiviral and proviral effects. This is modulated by both editing‐dependent and editing‐independent functions, such as PKR antagonism. Several A‐to‐I RNA editing events have been identified in viruses, including in the insidious viral pathogen, SARS‐CoV‐2 which regulates viral fitness and infectivity, and could play a role in shaping viral evolution. Furthermore, ADAR1 is an attractive target for immuno‐oncology therapy. Overexpression of ADAR1 and increased dsRNA editing have been observed in several human cancers. Silencing ADAR1, especially in cancers that are refractory to immune checkpoint inhibitors, is a promising therapeutic strategy for cancer immunotherapy in conjunction with epigenetic therapy. The mechanistic understanding of dsRNA editing by ADAR1 and dsRNA sensing by MDA5 and PKR holds great potential for therapeutic applications.This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease

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Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses

Cited by 84 publications

References 105 publications

Deciphering the Biological Significance of ADAR1–Z-RNA Interactions

Deciphering the Biological Significance of ADAR1–Z-RNA Interactions

Z‐nucleic acids: Uncovering the functions from past to present

A‐to‐I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy

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