Control of retrotransposon-driven activation of the interferon response by the double-stranded RNA binding protein DGCR8
Gazquez-Gutierrez, A.; Chin, P.; Peris, G.; Gordon, K.; Marchante, P. G.; Witteveldt, J.; Tristan-Ramos, P.; Rouviere, J. O.; Knol, L.; Ivens, A.; Lopez-Onieva, L.; Estevez, A. M.; Garland, W.; Jensen, T. H.; Heras, S. R.; Macias, S.
Show abstract
The type I interferon (IFN) response is the main innate immune pathway against viruses in mammals. This pathway must be tightly regulated to prevent viral spread while avoiding excessive immune responses. Here, we show that inactivation of the double-stranded RNA (dsRNA)-binding protein DGCR8 unleashes the IFN response in human cells. We demonstrate that DGCR8 restricts the accumulation of endogenous dsRNA originating from protein-coding mRNAs that harbour transposable elements (TEs), primarily Alu. We propose that DGCR8 binding to TE-rich mRNAs is essential to resolve dsRNA structures, and in its absence, accumulated dsRNA signals through the RIG-I-like signalling pathway triggering the IFN response. This mechanism is relevant to conditions where DGCR8 expression levels are altered, including the 22q11.2 deletion syndrome (22qDS). Supporting this, we show that 22qDS-derived cells exhibit an exacerbated type I IFN response which inversely correlated with DGCR8 levels. All these together demonstrate the importance of suppressing endogenous TE-dsRNA accumulation to prevent unwanted immune activation and associated disease pathogenesis.
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