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

Reuver, de; Dierick,; Wiernicki,; Staes,; Seys,; Meester, De; Muyldermans,; Botzki,; Lambrecht,; Nieuwerburgh, Van; Vandenabeele,; Maelfait,

doi:10.1101/2020.12.04.411702

Cited by 4 publications

(6 citation statements)

References 79 publications

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“…Subsequent experiments demonstrated that the mouse equivalent to the P193A variant recapitulated the human Zα mendelian phenotype [36]. Three other recently generated mouse models using different loss of function Zα residues variants also were associated with a type I interferon signature [37][38][39]. Taken together, the data confirmed the biological relevance of the Z-conformation and provided evidence for its role in the regulation of type I interferon responses.…”

Section: Adar1 and Human Diseasementioning

confidence: 70%

“…Then p150 stays mostly cytoplasmic as nuclear uptake is inhibited by the free dsRNA that accumulates in the absence of p110. This explanation is supported by the finding that in the Zα loss of function mice, which have normal p110 levels, the nuclear and cytoplasmic levels of p150 are the same as wild type [37].…”

Section: The Importance Of Adar1 P150mentioning

confidence: 80%

“…A common finding was that there was extensive overlap in the edits made by each isoform, with p150 edits occurring mostly in Alu elements, with around 50% occurring in 3 0 untranslated regions (UTRs) in mice [44,45]. The further analysis of p150 biology in mice with Zα loss of function variants was confounded by the presence of p110 that edits many substrates in common with p150 as expected from their shared dsRNA and deaminase domains [37][38][39]46]. In a technical tour de force, Kim and colleagues succeeded in creating a mouse that expressed only p150, but with no detectable p110 [47].…”

Section: The Importance Of Adar1 P150mentioning

confidence: 99%

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To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

Herbert

2021

PLoS Genet

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Double-stranded RNA (dsRNA) is produced both by virus and host. Its recognition by the melanoma differentiation–associated gene 5 (MDA5) initiates type I interferon responses. How can a host distinguish self-transcripts from nonself to ensure that responses are targeted correctly? Here, I discuss a role for MDA5 helicase in inducing Z-RNA formation by Alu inverted repeat (AIR) elements. These retroelements have highly conserved sequences that favor Z-formation, creating a site for the dsRNA-specific deaminase enzyme ADAR1 to dock. The subsequent editing destabilizes the dsRNA, ending further interaction with MDA5 and terminating innate immune responses directed against self. By enabling self-recognition, Alu retrotransposons, once invaders, now are genetic elements that keep immune responses in check. I also discuss the possible but less characterized roles of the other helicases in modulating innate immune responses, focusing on DExH-box helicase 9 (DHX9) and Mov10 RISC complex RNA helicase (MOV10). DHX9 and MOV10 function differently from MDA5, but still use nucleic acid structure, rather than nucleotide sequence, to define self. Those genetic elements encoding the alternative conformations involved, referred to as flipons, enable helicases to dynamically shape a cell’s repertoire of responses. In the case of MDA5, Alu flipons switch off the dsRNA-dependent responses against self. I suggest a number of genetic systems in which to study interactions between flipons and helicases further.

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Section: Adar1 and Human Diseasementioning

confidence: 70%

Section: The Importance Of Adar1 P150mentioning

confidence: 80%

Section: The Importance Of Adar1 P150mentioning

confidence: 99%

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To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

Herbert

2021

PLoS Genet

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“…RNA that adopts a non-canonical Z-conformation has increased immunostimulatory potential. The latter is reduced upon binding and editing by ADAR1 p150, which contains a Z-nucleic acid (Za) binding domain (de Reuver et al, 2021;Tang et al, 2021;Nakahama et al, 2021;Maurano et al, 2021;Zillinger & Bartok, 2021). In mice, various mutations in the Za domain of ADAR1 result in postnatal growth retardation and mortality as well as an increased type I IFN signature (de Reuver et al, 2021;Maurano et al, 2021;Nakahama et al, 2021;Tang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

RNA sensing via LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency

Stok

Oosenbrug

Haar

et al. 2021

Preprint

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RNA editing by the enzyme Adenosine Deaminase Acting on RNA 1 (ADAR1) is an important mechanism by which cells avoid innate immune responses to some endogenous RNAs. In ADAR1-deficient cells, unedited self RNAs can form base-paired structures that resemble viral RNAs and inadvertently activate antiviral innate immune pathways that lead to the induction of type I interferon (IFN). Rare mutations in ADAR1 cause Aicardi-Goutières Syndrome (AGS), a severe childhood autoinflammatory syndrome that is characterized by chronic and excessive type I IFN production and developmental delay. Conversely, ADAR1 dysfunction and consequent type I IFN production helps restrict tumor growth and potentiates the activity of some chemotherapy drugs. Induction of type I IFN in ADAR1-deficient cells is thought to be due to triggering of the cytosolic RIG-I-like receptor (RLR), MDA5, by unedited self RNAs. Here, we show that another RLR, LGP2, also has an essential role. We demonstrate that ADAR1-deficient human cells fail to mount a type I IFN response in the absence of LGP2 and this involves the canonical function of LGP2 as an RNA sensor and facilitator of MDA5-dependent signaling. Further, we show that the sensitivity of tumor cells to ADAR1 loss requires the presence of LGP2. Finally, we find that type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics is fully dependent on the expression of LGP2. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications for the treatment of AGS as well as for the potential application of ADAR1-directed anti-tumor therapy.

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“…In particular, when other cell death pathways are inactivated by mutation, necroptosis that is dependent on ZBP1 produces inflammation and disease due to necroptosis. Other labs (Jon Maelfait [ 21 ], Jan Rehwinkel [ 22 ] and Andrew Oberst (unpublished) presented studies from mouse models to examine the genetic interactions between ZBP1, MDA5 and ADAR1 and their outcomes, in particular on live births. Preliminary results were presented showing that in certain crosses, embryonic lethality was associated with high interferon responses in the mother but not dependent on the paternal genotype.…”

Section: Meeting Summarymentioning

confidence: 99%

Special Issue: A, B and Z: The Structure, Function and Genetics of Z-DNA and Z-RNA

Herbert

Karapetyan

Poptsova

et al. 2021

IJMS

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It is now difficult to believe that a biological function for the left-handed Z-DNA and Z-RNA conformations was once controversial. The papers in this Special Issue, “Z-DNA and Z-RNA: from Physical Structure to Biological Function”, are based on presentations at the ABZ2021 meeting that was held virtually on 19 May 2021 and provide evidence for several biological functions of these structures. The first of its kind, this international conference gathered over 200 scientists from many disciplines to specifically address progress in research involving Z-DNA and Z-RNA. These high-energy left-handed conformers of B-DNA and A-RNA are associated with biological functions and disease outcomes, as evidenced from both mouse and human genetic studies. These alternative structures, referred to as “flipons”, form under physiological conditions, regulate type I interferon responses and induce necroptosis during viral infection. They can also stimulate genetic instability, resulting in adaptive evolution and diseases such as cancer. The meeting featured cutting-edge science that was, for the most part, unpublished. We plan for the ABZ meeting to reconvene in 2022.

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

Cited by 4 publications

References 79 publications

To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

RNA sensing via LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency

Special Issue: A, B and Z: The Structure, Function and Genetics of Z-DNA and Z-RNA

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