RNA Sensing Via the RIG-I-like Receptor LGP2 is Essential for the Induction of a Type I IFN Response in ADAR1 Deficiency

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2022 Feb 14

PMID 35156720

Authors

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

Affiliations

Soon will be listed here.

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.

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