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    Home > Active Ingredient News > Immunology News > Three articles on Immunity Z-RNA editing restrict innate immunity from recognizing endogenous RNA

    Three articles on Immunity Z-RNA editing restrict innate immunity from recognizing endogenous RNA

    • Last Update: 2021-11-15
    • Source: Internet
    • Author: User
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    Written | King Koala's Eucalyptus The human innate immune system monitors the abnormal nucleic acid molecules in the cells to detect the invasion of pathogens
    .

    The double-stranded nucleic acid molecule in the cell will form an abnormal conformation of Z-DNA and Z-RNA, which in turn activates the innate immune response
    .

    Unlike the classic B-DNA (right-handed double helix), Z-DNA is a left-handed double helix with a zigzag phosphodiester skeleton structure [1]
    .

    The biological function of Z nucleic acid, especially Z-RNA, is still unknown
    .

    A small number of proteins involved in innate immunity contain Z-DNA and Z-RNA binding domains called Zα [2], which specifically bind and stabilize Z-DNA and Z-RNA [3]
    .

    There are two proteins with Zα domains in mammals: Z-DNA binding protein 1 (ZBP1) and RNA adenosine deaminase 1 (ADAR1)
    .

    ADAR1 has two splicing subtypes: ADAR1-p110, which is continuously expressed and localized in the nucleus; ADAR1-p150, IFN (interferons) is induced to express and exists in the nucleus and cytoplasm
    .

    The N-terminal of ADAR1-p150 contains a Zα domain.
    In humans, ADAR1 mutations can cause AGS (Aicardi-Goutières syndrome), and the most common ADAR1 mutation (P193A) in AGS patients is located in the Zα domain [4]
    .

    However, how the different nucleic acid binding domains in ADAR1 select and recruit RNA substrates for subsequent editing and their functions are unclear
    .

    Therefore, studying the specific contribution of the Zα domain to RNA may provide a wealth of information about the immune function of ADAR1
    .

    Recently, three studies published in Immunity also reported that mutations in the Zα-RNA binding domain of ADAR1 are sufficient to induce auto-inflammation in mice.
    These mutations mimic the human Aicardí-Goutières syndrome and highlight the innate effect of Z-RNA editing.
    Important role in immune recognition
    .

    This article focuses on the research work of Jan Rehwinkel's research group at Oxford University Radcliffe Medical School: Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses.
    They constructed Zα- There are two mouse models with missense mutations in the RNA domain.
    It was found that these mice spontaneously induce type I IFNs and ISGs in multiple organs and cell types, suggesting that Z-RNA editing is restricting the recognition of endogenous RNA by innate immunity The important role of aspects
    .

    In order to study the interaction between Z-RNA and the Zα domain of ADAR1-p150 in vivo, the authors constructed a mouse model mZα with two missense mutations in ADAR1: p.
    Asn175Ala and p.
    Tyr179Ala
    .

    These residues play an important role in Z-type nucleic acid binding and are homologous to Asn173 and Tyr177 in human ADAR1
    .

    The authors found that ADAR1-p150 binding to Z-RNA is not necessary for survival at the whole organism level
    .

    They then tested whether Adar1mZα/mZα mice spontaneously activate type I IFNs
    .

    By collecting lung, liver, spleen and other tissues, RNA was extracted for qRT-PCR analysis
    .

    In Adar1mZα/mZα mouse lung RNA samples, the transcription level of Ifnb1 (encoding IFNβ) was significantly increased
    .

    There are differences in the expression levels of ISG (IFN-stimulated genes) in different types of primary cells, and the expression of ISG is increased in lung fibroblasts with mutations in the Zα domain
    .

    For embryonic fibroblasts, similar levels of ISG were detected in WT and Adar1mZα/mZα cells, indicating that ISG induction has cell type specificity
    .

    Among different organs, the lung showed the strongest ISG characteristics, and spontaneous ISG induction was also observed in cultured lung fibroblasts
    .

    Therefore, the author focused his research on the lungs for follow-up experiments
    .

    In order to obtain the overall situation of gene expression in Adar1mZα/mZα mice, the authors extracted RNA from the lungs for RNA sequencing analysis
    .

    Sequencing results showed that the lung tissues of animals with Zα domain mutations showed gene characteristics driven by type I IFNs
    .

    In order to identify the cell types that show ISG signals in the lungs of Adar1mZα/mZα mice, the authors used MACS to isolate different cells in the lungs
    .

    Through different types of cells, it was found that in the lungs of Adar1mZα/mZα mice, a variety of cells such as hematopoietic cells and stromal cells would initiate type I IFN responses
    .

    In order to further analyze the cellular requirements of Adar1mZα/mZα mice for ISG induction, the authors constructed a bone marrow chimeric animal model and found that hematopoietic cells in Adar1mZα/mZα mice were sufficient to induce wild-type mice to produce ISG signals
    .

    In view of the spontaneous type I IFN response of Adar1mZα/mZα mice, the authors explored whether the Zα domain mutant mice have a protective effect on viral infection
    .

    The experimental results suggest that Adar1mZα/mZα mice are protected in the early stage of IAV infection
    .

    Compared with wild-type mice, Adar1mZα/mZα mice have reduced IAV replication and virus-induced inflammation
    .

    Next, the authors investigated which nucleic acid sensing pathways trigger spontaneous ISG expression in Adar1mZα/mZα mice
    .

    Because the absence of ADAR1 will cause the activation of the MDA5-MAVS pathway [5], the authors hypothesized that the ISG signal of ADAR1 mZα/mZα mice is driven by MAVS
    .

    To verify this, they crossed ADAR1 mutant mice with Mavs−/− mice, and observed in Adar1mZα/mZα lungs, liver, and spleen that the absence of MAVS prevented the induction of ISG
    .

    It shows that the Zα domain of ADAR1-p150 is involved in preventing MAVS-mediated IFN induction
    .

    Finally, in order to identify natural RNA substrates edited by ADAR1-p150 in a Zα domain-dependent manner, the authors analyzed RNA-seq data from WT and Adar1mZα/mZα lungs
    .

    In both WT and Adar1mZα/mZα samples, the median editing level of these sites was 10%, indicating that there is no overall defect in RNA editing in Adar1mZα/mZα mice
    .

    By comparing the editing sites of WT and mutant mice, it is found that about 8% of editing sites require ADAR1-p150 with a complete Zα domain for effective editing
    .

    In summary, although Z-nucleic acid was discovered 40 years ago, little is known about its biological function
    .

    In this paper, by introducing mutations into the Zα domain of ADAR1-p150 to prevent it from binding to Z-RNA, it is revealed that type I IFN induction is a biological function of Z-RNA
    .

    Three studies published in Immunity at the same time revealed the effects of functional mutations in the Zα domain of mouse Adar1 p150 by using three different mutagenesis methods
    .

    The consistency of these findings highlights the important role of Z-RNA editing in limiting the innate immune recognition of endogenous RNA
    .

    At the same time, some surprising and different results have led to more new problems
    .

    Original link: https://doi.
    org/10.
    1016/j.
    immuni.
    2021.
    08.
    011https://doi.
    org/10.
    1016/j.
    immuni.
    2021.
    08.
    022https://doi.
    org/10.
    1016/j.
    immuni.
    2021.
    07 .
    001 Platemaker: Eleven References 1.
    Wang AHJ, Quigley GJ, Kolpak FJ, et al.
    Molecular structure of a left-handed double helical DNA fragment at atomic resolution[J].
    Nature, 1979, 282(5740): 680-686.
    2.
    Athanasiadis A.
    Zalpha-domains: at the intersection between RNA editing and innate immunity[C]//Seminars in cell & developmental biology.
    Academic Press, 2012, 23(3): 275-280.
    3.
    Brown, Bernard A .
    , et al.
    "The Zα domain of the editing enzyme dsRNA adenosine deaminase binds left-handed Z-RNA as well as Z-DNA.
    " Proceedings of the National Academy of Sciences 97.
    25 (2000): 13532-13536.
    4.
    Rice, Gillian I.
    , et al.
    "Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature.
    "Nature genetics 44.
    11 (2012): 1243-1248.
    5.
    Liddicoat, Brian J.
    , et al.
    "RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself.
    " Science 349.
    6252 (2015): 1115-1120.
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