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

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    Authors
    Stok, J. E.
    Oosenbrug, T.
    Ter Haar, L. R.
    Gravekamp, D.
    Bromley, Christian P
    Zelenay, Santiago
    Reis, E. S. C.
    van der Veen, A. G.
    Affiliation
    Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands. Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, UK. Immunobiology Laboratory, The Francis Crick Institute, London, UK.
    Issue Date
    2022
    
    Metadata
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    Abstract
    RNA editing by the adenosine deaminase ADAR1 prevents innate immune responses to endogenous RNAs. In ADAR1-deficient cells, unedited self RNAs form base-paired structures that resemble viral RNAs and inadvertently activate the cytosolic RIG-I-like receptor (RLR) MDA5, leading to an antiviral type I interferon (IFN) response. Mutations in ADAR1 cause Aicardi-Goutières Syndrome (AGS), an autoinflammatory syndrome characterized by chronic type I IFN production. Conversely, ADAR1 loss and the consequent type I IFN production restricts tumor growth and potentiates the activity of some chemotherapeutics. Here, we show that another RIG-I-like receptor, LGP2, also has an essential role in the induction of a type I IFN response in ADAR1-deficient human cells. This requires the canonical function of LGP2 as an RNA sensor and facilitator of MDA5-dependent signaling. Furthermore, we show that the sensitivity of tumor cells to ADAR1 loss requires LGP2 expression. Finally, type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics fully depends on LGP2 expression. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications.
    Citation
    Stok JE, Oosenbrug T, Haar LR, Gravekamp D, Bromley CP, Zelenay S, et al. RNA sensing via the RIG‐I‐like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency [Internet]. The EMBO Journal. EMBO; 2022.
    Journal
    Embo Journal
    URI
    http://hdl.handle.net/10541/625137
    DOI
    10.15252/embj.2021109760
    PubMed ID
    35156720
    Additional Links
    https://dx.doi.org/10.15252/embj.2021109760
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.15252/embj.2021109760
    Scopus Count
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    All Paterson Institute for Cancer Research

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