RNA sensing via the RIG-I-like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency
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
Show full item recordAbstract
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 JournalDOI
10.15252/embj.2021109760PubMed ID
35156720Additional Links
https://dx.doi.org/10.15252/embj.2021109760Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.15252/embj.2021109760
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