The innate immunity response to viral infection in mammalian cells relies on the expression of interferon-stimulated genes; notably, this response is limited in stem cells. Invertebrates and plants also lack antiviral interferon responses, instead relying on RNAi to combat RNA viruses. Poirier et al. now show that an isoform of the RNAi protein Dicer limits virus infection in mammalian stem cells.
Mammals encode one canonical Dicer, which is an RNase that processes precursor-microRNAs but has low capacity for processing double-stranded RNA (dsRNA) into siRNAs, as this activity is suppressed by its own helicase domain. The authors identified an alternatively spliced, in-frame transcript encoding a Dicer lacking part of its helicase domain, and found it is expressed in various mouse and human cells types. They named this isoform antiviral Dicer (aviD), as recombinant aviD produced about twice as much siRNA in vitro compared with recombinant Dicer.
To test the relevance of aviD to viral infection, human embryonic kidney (HEK) cells lacking the DICER gene but complemented with either aviD or Dicer were infected with Sindbis virus or with Zika virus (ZIKV). Lower virus titres were observed in cells expressing aviD than in cells expressing Dicer or a catalytically deficient aviD. Furthermore, DICER-null HEK cells engineered to express the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptor ACE2, and expressing aviD, were three times less infected by SARS-CoV-2 than their Dicer-expressing counterparts.
In mice, aviD mRNA was expressed predominantly in various LGR5+ or SOX2+ stem cells, and in brain organoids, SOX2+ neural stem cells expressed more aviD transcripts than differentiated cells. Upon ZIKV infection, wild-type brain organoids grew quicker and produced lower virus titres than Dicer+/+aviD–/– organoids, despite their low level of endogenous aviD expression. In Dicer+/+aviD–/– organoids, SOX2+ stem cells displayed increased infection with ZIKV and accumulated more viral dsRNA and less viral siRNAs than in aviD-expressing organoids. Absence of aviD also promoted SARS-CoV-2 infection of ACE2+ embryonic stem cell-derived brain organoids.
“an isoform of … Dicer limits virus infection in mammalian stem cells”
In summary, an aviD-mediated RNAi response helps protect mammalian stem cells against RNA virus infection.
Poirier, E. Z. et al. An isoform of Dicer protects mammalian stem cells against multiple RNA viruses. Science 373, 231–236 (2021)
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Zlotorynski, E. Dicing viral RNA in stem cells. Nat Rev Mol Cell Biol 22, 586 (2021). https://doi.org/10.1038/s41580-021-00406-1