MicroRNA-deficient mouse embryonic stem cells acquire a functional interferon response

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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.

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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files for Figure 3B are included in the Supplementary Excel File

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Jeroen Witteveldt

Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Lisanne I Knol

Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8975-0398
Sara Macias

Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom

For correspondence
sara.maciasribela@ed.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0643-3494

Funding

Wellcome (107665/Z/15/Z)

Sara Macias

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.