Abstract
When mammalian cells detect a viral infection, they initiate a type I interferon (IFNs) response as part of their innate immune system. This antiviral mechanism is conserved in virtually all cell types, except for embryonic stem cells (ESCs) and oocytes which are intrinsically incapable of producing IFNs. Despite the importance of the IFN response to fight viral infections, the mechanisms regulating this pathway during pluripotency are still unknown. Here we show that, in the absence of miRNAs, ESCs acquire an active IFN response. Proteomic analysis identified MAVS, a central component of the IFN pathway, to be actively silenced by miRNAs and responsible for suppressing IFN expression in ESCs. Furthermore, we show that knocking out a single miRNA, miR-673, restores the antiviral response in ESCs through MAVS regulation. Our findings suggest that the interaction between miR-673 and MAVS acts as a switch to suppress the antiviral IFN during pluripotency and present genetic approaches to enhance their antiviral immunity.
Highlights
Type-I Interferons (IFN) are crucial cytokines of the innate antiviral response
We found that miRNA-deficient embryonic stem cells (ESCs) acquire an IFN-proficient state, are able to synthesize IFN-β and mount a functional antiviral response
We aimed to identify the miRNA(s) responsible for the regulation of Mitochondrial antiviral-signalling protein (MAVS) in ESCs and selected a number of miRNA candidates based on literature, prediction software and public miRNA expression databases for further investigations
Summary
Type-I Interferons (IFN) are crucial cytokines of the innate antiviral response. Most mammalian cell types are capable of synthesizing type-I IFNs in response to invading viruses and other pathogens. Once type-I IFNs are secreted, they activate the JAK-STAT pathway and production of Interferon-stimulated genes (ISGs) in both the infected and neighbouring cells to induce an antiviral state (Ivashkiv and Donlin, 2015). Two major signalling pathways are involved in IFN production in the context of viral infections. The dsRNA sensors RIG-I and MDA5 initiate a signalling cascade that signals through the central mitochondrial-associated factor MAVS, activating Ifnb-1 transcription. The protein (Chan and Gack, 2016)
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