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

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

  • EMBO J. 2022 Mar 15;41(6):e109760. doi: 10.15252/embj.2021109760.
Jorn E Stok  # 1 Timo Oosenbrug  # 1 Laurens R Ter Haar 1 Dennis Gravekamp 1 Christian P Bromley 2 Santiago Zelenay 2 Caetano Reis E Sousa 3 Annemarthe G van der Veen 1
Affiliations

Affiliations

  • 1 Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands.
  • 2 Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, UK.
  • 3 Immunobiology Laboratory, The Francis Crick Institute, London, UK.
  • # Contributed equally.
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.

Keywords

RIG-I-like receptor family; RNA editing; autoinflammation; innate immunity; type I interferon.

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