The EMBO Journal - 2022 - Stok - RNA sensing via the RIG‐I‐like receptor LGP2 is essential for the induction of a type I.pdf (1.79 MB)
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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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journal contribution
posted on 16.03.2022, 12:04 authored by Jorn E Stok, Timo Oosenbrug, Laurens R ter Haar, Dennis Gravekamp, Christian P Bromley, Santiago Zelenay, Caetano Reis e Sousa, Annemarthe G van der Veen
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.

Funding

Crick (Grant ID: 10136, Grant title: Reis e Sousa FC001136) European Research Council (Grant ID: 786674 - DCPOIESIS, Grant title: ERC 786674 - DCPOIESIS) Wellcome Trust (Grant ID: 106973/Z/15/Z, Grant title: WT 106973/Z/15/Z)

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