Presplicing factors associate with UpA-rich RNA and limit flavivirus replication
- 1Laboratory of Virology, Wageningen University & Research, P.O. Box 16, Wageningen, 6700 AA The Netherlands
- 2Laboratory of Biochemistry, Wageningen University & Research, Postal address: Box 8128, Wageningen, 6700 ET, The Netherlands
Abstract
The RNA of all living organisms and most viruses exhibits pervasive suppression of uracil-adenine (UpA) dinucleotides, yet the underlying molecular mechanisms remain poorly understood. Here, we use RNA affinity purification coupled with mass spectrometry to identify diverse host factors that preferentially bind UpA-high RNA sequences. The identified proteins include the canonical antiviral proteins IFIT1 and OAS1, as well as multiple components of the U1 and U2 small nuclear ribonucleoproteins (snRNPs), core elements of the splicing machinery. These splicing factors display increased affinity for artificially UpA-enriched RNA and the West Nile virus (WNV) 3’ UTR, which naturally contains higher frequencies of UpA dinucleotides. The functional relevance of splicing factor interactions was demonstrated by pharmacological inhibition of early splicing events, which partially restored the replicative fitness of synonymously recoded and otherwise attenuated UpA-high mutants of Zika virus and WNV. Together, these findings reveal a novel antiviral role for splicing factors, linking their preferential association with UpA-rich RNA to the restriction of UpA-high viruses. Given the evolutionary conservation of the splicing machinery, our results suggest that splicing factor-mediated recognition may contribute to maintain the universal suppression of UpA dinucleotides in host and viral RNA.
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BibTeX
@article{bree2026presplicing,
title = {{Presplicing factors associate with UpA-rich RNA and limit flavivirus replication}},
author = {Joyce W.M. van Bree and Kristel Doets and Carmen van de Waterbeemd and Sjef Boeren and Monique M. van Oers and Gorben P. Pijlman and Jelke J. Fros},
journal = {Molecules and Cells},
year = {2026},
month = oct,
doi = {10.1016/j.mocell.2026.100404},
url = {https://doi.org/10.1016/j.mocell.2026.100404},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Presplicing factors associate with UpA-rich RNA and limit flavivirus replication
AU - Joyce W.M. van Bree
AU - Kristel Doets
AU - Carmen van de Waterbeemd
AU - Sjef Boeren
AU - Monique M. van Oers
AU - Gorben P. Pijlman
AU - Jelke J. Fros
PY - 2026
DA - 2026/10/05
JO - Molecules and Cells
DO - 10.1016/j.mocell.2026.100404
UR - https://doi.org/10.1016/j.mocell.2026.100404
AB - The RNA of all living organisms and most viruses exhibits pervasive suppression of uracil-adenine (UpA) dinucleotides, yet the underlying molecular mechanisms remain poorly understood. Here, we use RNA affinity purification coupled with mass spectrometry to identify diverse host factors that preferentially bind UpA-high RNA sequences. The identified proteins include the canonical antiviral proteins IFIT1 and OAS1, as well as multiple components of the U1 and U2 small nuclear ribonucleoproteins (snRNPs), core elements of the splicing machinery. These splicing factors display increased affinity for artificially UpA-enriched RNA and the West Nile virus (WNV) 3’ UTR, which naturally contains higher frequencies of UpA dinucleotides. The functional relevance of splicing factor interactions was demonstrated by pharmacological inhibition of early splicing events, which partially restored the replicative fitness of synonymously recoded and otherwise attenuated UpA-high mutants of Zika virus and WNV. Together, these findings reveal a novel antiviral role for splicing factors, linking their preferential association with UpA-rich RNA to the restriction of UpA-high viruses. Given the evolutionary conservation of the splicing machinery, our results suggest that splicing factor-mediated recognition may contribute to maintain the universal suppression of UpA dinucleotides in host and viral RNA.
SN - 1016-8478
SN - 0219-1032
ER -