ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation

Reuver, Richard de; Dierick, Evelien; Wiernicki, Bartosz; Staes, Katrien; Seys, Leen; Meester, Ellen De; Muyldermans, Tuur; Botzki, Alexander; Lambrecht, Bart; Nieuwerburgh, Filip Van; Vandenabeele, Peter; Maelfait, Jonathan

doi:10.1016/j.celrep.2021.109500

Cited by 85 publications

(114 citation statements)

References 81 publications

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“…Although cytoplasm-dominant localization and expression level are not affected by W197A substitution, the RNA-editing activity of ADAR1 p150 (W197A) is significantly lower than that of the wild-type at selective sites [ 77 ]. Furthermore, de Reuver et al inserted Y177A with/without N173A mutations into ADAR1 p150 in human HEK293 cells and compared RNA-editing activity between wild-type ADAR1 p150 (WT) and Zα-mutated ADAR1 p150 after increasing the amount of ADAR1 p150 by the addition of IFN-α2 [ 78 ]. This analysis demonstrates that although the number of RNA-editing sites, including ADAR1 p110- and ADAR2-responsible sites, is not largely different, RNA editing in the 3′UTR seems more affected than in other regions.…”

Section: Zα Contributes To Adar1 P150-mediated Rna Editingmentioning

confidence: 99%

“…This analysis demonstrates that although the number of RNA-editing sites, including ADAR1 p110- and ADAR2-responsible sites, is not largely different, RNA editing in the 3′UTR seems more affected than in other regions. In addition, Zα-mutated ADAR1 p150-expressing HEK293 cells are more sensitive to the increased amount of MDA5 than wild-type cells [ 78 ]. Notably, the expression of dsRBD-mutated ADAR1 p150, in which Zα is intact, cannot edit any sites in Adar1/Adar2 dKO Raw 264.7 cells, suggesting that the presence of Zα alone is not sufficient to induce RNA editing [ 77 ].…”

Section: Zα Contributes To Adar1 P150-mediated Rna Editingmentioning

confidence: 99%

“…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%

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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: Zα Contributes To Adar1 P150-mediated Rna Editingmentioning

confidence: 99%

Section: Zα Contributes To Adar1 P150-mediated Rna Editingmentioning

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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Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment

Hariharan

Rehrauer

et al. 2022

Molecular Oncology

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We previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures.

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

Tang

2022

Eur J Immunol

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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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ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation

Cited by 85 publications

References 81 publications

Deciphering the Biological Significance of ADAR1–Z-RNA Interactions

Deciphering the Biological Significance of ADAR1–Z-RNA Interactions

Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment

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

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