UncoveRNAi · Deciphering the mechanisms of antiviral RNA interference in mammals

Deciphering the mechanisms of antiviral RNA interference in mammals

Introduction, objectives and importance Stem cells play a fundamental role in the maintenance of adult tissue architecture and integrity by providing a pool of differentiated cells through asymmetric division (1). Therefore, they must shield from endogenous threats, such as transposable elements, as well as from exogenous insults, e.g. genotoxic stress or viral infections. Early antiviral responses in mammals rely on the expression of type I and type III interferons (IFN), which act on differentiated cells in an autocrine and paracrine manner to promote the transcription of interferon stimulated genes (ISGs) that encode antiviral effector proteins (2). However, protection conferred by the IFN pathway is severely compromised in embryonic and adult stem cells, which lack key components of the pathway (3). IFN incompetence may ensure that stem cells are protected from the cytostatic properties of IFN, such as antiproliferative and proapoptotic effects. Despite their IFN unresponsiveness, stem cells are largely resistant to viral infection, which can be attributed in part to the steady-state expression of ISGs and other factors restricting infection (4). Nonetheless, immune responses in stem cells remain poorly characterised. In invertebrates and plants, antiviral immunity relies on RNA interference (RNAi), which is initiated by the cleavage of viral double-stranded RNA (dsRNA) by a Dicer protein, generating small interfering RNAs (siRNAs) which guide the degradation of viral RNA (3). Irrespective of infection, RNAi also has a role in regulating cellular gene expression via micro RNAs (miRNAs) produced by Dicer through cleavage of pre-miRNAs. Organisms that use RNAi both as an antiviral response and as a way of regulating mRNA translation with miRNAs have several Dicer genes, the product of which are dedicated to processing either dsRNA or pre-miRNAs (5). In mammals, a single Dicer gene has been described, which encodes a Dicer protein that generates miRNAs but cleaves dsRNA only poorly (6). Whether antiviral RNAi exists in mammalian cells and is relevant to immunity remains highly controversial (3). This project aims at delineating the role and importance of antiviral RNAi in mammals, by answering three mains questions: where does antiviral RNAi happen in vivo, how does it happen, and what is its importance in antiviral immunity compare to IFN activation. Understanding the role and importance of antiviral RNAi in mammals will advance basic knowledge of mammalian immunity, and could also pave the way to innovative antiviral therapies in humans. Conclusions of the action An novel isoform of Dicer, termed antiviral Dicer (aviD) was discovered in the course of this work. This isoform is expressed in mouse and human stem cells within tissues, and protects them against viruses such as Zika virus or severe acute respiratory syndrome coronavirus 2, by implementing canonical antiviral RNAi. References 1. E. Batlle, H. Clevers, Nat. Med. 23, 1124–1134 (2017). 2. X. Tan, L. Sun, J. Chen, Z. J. Chen, Annu. Rev. Microbiol. 72, 447–478 (2018). 3. P. V. Maillard, A. G. Veen, E. Z. Poirier, C. Reis e Sousa, EMBO J. 38 (2019), doi:10.15252/embj.2018100941. 4. X. Wu et al., Cell (2017), doi:10.1016/j.cell.2017.11.018. 5. S.-W. Ding, Nat. Rev. Immunol. 10, 632–644 (2010). 6. E. Ma, I. J. MacRae, J. F. Kirsch, J. A. Doudna, J. Mol. Biol. 380, 237–243 (2008).

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