DGCR8 controls retrotransposon-derived double-stranded RNA accumulation and interferon activation

The type I interferon (IFN) response is the main innate immune pathway against viruses in mammals and must be tightly regulated to stop viral spread without excessive immune reaction. Here, we show that inactivation of the double-stranded RNA (dsRNA)-binding protein DGCR8 unleashes the IFN response in human cells. Remarkably, we demonstrate that, independently of its function in miRNA biogenesis, DGCR8 prevents the accumulation of endogenous dsRNA. These dsRNAs derive from protein-coding mRNAs enriched in transposable elements (TEs), mostly Alu elements. We propose that DGCR8 binding to TE-rich mRNAs is key to resolve dsRNA structures. In the absence of DGCR8, these unresolved dsRNAs signal through the RIG-I-like signalling pathway triggering the IFN response. This mechanism may be particularly relevant to conditions such as the 22q11.2 deletion syndrome (22qDS), where DGCR8 expression is reduced. Supporting this, we show that cells derived from 22qDS patients exhibit an exacerbated type I IFN response, highlighting the importance of suppressing endogenous dsRNA accumulation to prevent unwanted immune activation.