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Control of retrotransposon-driven activation of the interferon response by the double-stranded RNA binding protein DGCR8

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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Jeroen Witteveldt

LAB HEAD: Sara Macias

PROVIDER: PXD074388 | Pride | 2026-02-12

REPOSITORIES: Pride

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

Project description: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.

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Silencing of double stranded RNA sensing is required for early embryonic development

Project description:The type I interferon (IFN) response is inactive during early mammalian development and becomes functional only after gastrulation. As a result, the totipotent and pluripotent embryonic stages remain susceptible to pathogens, including viruses. Here, we demonstrate that pluripotent mouse embryonic stem cells (mESCs) suppress the RIG-I-like receptor sensing pathway by silencing the expression of the dsRNA sensor MDA5. This silencing is necessary to avoid the recognition of dsRNAs of endogenous origin, which accumulate in mESCs. Reintroducing MDA5 results in recognition of these endogenous dsRNAs and triggers the activation of the IFN response through IRF3. The production of IFN alters the differentiation ability of mESCs, and affects the pluripotency gene expression program, as shown by epigenetic, transcriptomic and proteomic analyses. These findings are conserved in zebrafish, where MDA5 is also expressed at later developmental stages. Similarly, zebrafish lack earlystage IFN activation, and dsRNA-mediated signalling results in developmental defects. Altogether, we conclude that silencing the RIG-I-like receptor pathway during early development is widely conserved and is essential to prevent aberrant immune recognition of endogenous dsRNAs, safeguarding normal development.

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Project description:In A. thaliana, C. elegans and Drosophila, long dsRNA accumulation during virus infection, transposon activation or transgene expression, elicits a potent RNAi response: long dsRNA processing into siRNAs by Dicer, loading into Argonaute and assembly of the RNA-induced silencing complex to slice complementary RNA. In mammals, recognition of long dsRNA by type I interferon (IFN) factors, results in a mitigated RNAi response in some cell types. Here we uncover key mechanisms associated with recognition and processing of long dsRNA by both pathways. First, we demonstrate that exogenous long dsRNA rapidly congregates into granules recruiting key RNA silencing and type I IFN factors, suggesting an interaction between these pathways. Second, we confirm that inactivation of PKR, unleashes a potent RNAi response on transgene and endogenous mRNA targets in HEK293T cells. Finally, we observe different Dicer processing modes and uncovered a role for TRBP as regulator of RNAi in a template-dependent manner.

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Project description:The type I interferon (IFN) response is inactive during early mammalian development and becomes functional only after gastrulation. As a result, the totipotent and pluripotent embryonic stages remain susceptible to pathogens, including viruses. Here, we demonstrate that pluripotent mouse embryonic stem cells (mESCs) suppress the RIG-I-like receptor sensing pathway by silencing the expression of the dsRNA sensor MDA5. This silencing is necessary to avoid the recognition of dsRNAs of endogenous origin, which accumulate in mESCs. Reintroducing MDA5 results in recognition of these endogenous dsRNAs and triggers the activation of the IFN response through IRF3. The production of IFN alters the differentiation ability of mESCs, and affects the pluripotency gene expression program, as shown by epigenetic, transcriptomic and proteomic analyses. These findings are conserved in zebrafish, where MDA5 is also expressed at later developmental stages. Similarly, zebrafish lack early-stage IFN activation, and dsRNA-mediated signalling results in developmental defects. Altogether, we conclude that silencing the RIG-I-like receptor pathway during early development is widely conserved and is essential to prevent aberrant immune recognition of endogenous dsRNAs, safeguarding normal development.

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