Abstract
In recent years, transcriptome profiling studies have identified changes in host splicing patterns caused by viral invasion, yet the functional consequences of the vast majority of these splicing events remain uncharacterized. We recently showed that the host splicing landscape changes during Rift Valley fever virus MP-12 strain (RVFV MP-12) infection of mammalian cells. Of particular interest, we observed that the host mRNA for Rio Kinase 3 (RIOK3) was alternatively spliced during infection. This kinase has been shown to be involved in pattern recognition receptor (PRR) signaling mediated by RIG-I like receptors to produce type-I interferon. Here, we characterize RIOK3 as an important component of the interferon signaling pathway during RVFV infection and demonstrate that RIOK3 mRNA expression is skewed shortly after infection to produce alternatively spliced variants that encode premature termination codons. This splicing event plays a critical role in regulation of the antiviral response. Interestingly, infection with other RNA viruses and transfection with nucleic acid-based RIG-I agonists also stimulated RIOK3 alternative splicing. Finally, we show that specifically stimulating alternative splicing of the RIOK3 transcript using a morpholino oligonucleotide reduced interferon expression. Collectively, these results indicate that RIOK3 is an important component of the mammalian interferon signaling cascade and its splicing is a potent regulatory mechanism capable of fine-tuning the host interferon response.
| Original language | English |
|---|---|
| Article number | 367 |
| Journal | Viruses |
| Volume | 13 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2021 |
Funding
for this research is from NIH grants R15AI105737, R03TR002937 and 4UT2GM130166-02 (Subaward GM130166) to JSL and P20GM103546 (S. Sprang, P.I.; JSL Pilot Project P.I.). We thank Miyuki Hayashi and Hunter Grimes for critical reading of the manuscript and Brian Gowen (Utah State University) for the gift of the MP-12 strain of RVFV, and Benjamin Brennan and Richard Elliott (then at University of St. Andrews) for the gift of the delNSsrLuc MP-12 strain of RVFV. We thank Jack Nunberg and Brent Ryckman (University of Mon-tana) for helpful discussions and the gifts of TCRV and ADV, and HCMV stocks, and gratefully acknowledge BEI Resources, NIAID, NIH for supplying the Sindbis virus EgAr 339, NR-15695. We thank the researchers who made constructs available in Addgene, as specified in the Materials and Methods. Funding: Funding for this research is from NIH grants R15AI105737, R03TR002937 and 4UT2GM130166-02 (Subaward GM130166) to JSL and P20GM103546 (S. Sprang, P.I.; JSL Pilot Project P.I.).
| Funder number |
|---|
| R03TR002937, 4UT2GM130166-02 |
| P20GM103546 |
| NR-15695, R15AI105737, EgAr 339 |
Keywords
- Alternative splicing
- Innate immune response
- MP-12
- Morpholino oligonucleotide
- RIOK3
- Rift Valley fever virus
