Abstract
Rift Valley fever virus (RVFV) is an emerging pathogen that has potential to cause severe disease in humans and domestic livestock. Propagation of RVFV strain MP-12 is negatively impacted by the actions of RIOK3, a protein involved in the cellular immune response to viral infection. During RVFV infection, RIOK3 mRNA is alternatively spliced to produce an isoform that correlates with the inhibition of interferon β signaling. Here, we identify splicing factor TRA2-β (also known as TRA2beta and hTRA2-β) as a key regulator governing the relative abundance of RIOK3 splicing isoforms. Using RT-PCR and minigenes, we determined that TRA2-β interaction with RIOK3 pre-mRNA was necessary for constitutive splicing of RIOK3 mRNA, and conversely, lack of TRA2-β engagement led to increased alternative splicing. Expression of TRA2-β was found to be necessary for RIOK3’s antiviral effect against RVFV. Intriguingly, TRA2-β mRNA is also alternatively spliced during RVFV infection, leading to a decrease in cellular TRA2-β protein levels. These results suggest that splicing modulation serves as an immune evasion strategy by RVFV and/or is a cellular mechanism to prevent excessive immune response. Furthermore, the results suggest that TRA2-β can act as a key regulator of additional steps of the innate immune response to viral infection.
Highlights
Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus (Order Bunyavirales; Family Phenuiviridae) (Adams et al, 2017) that is endemic to Africa and the Arabian Peninsula and causes disease in livestock and humans
We previously demonstrated that Rio kinase 3 (RIOK3) plays an important role in the cellular response to RVFV infection
We examined RIOK3 alternative splicing in the context of RVFV infection and observed that splice site selection in this gene is at least partially controlled by the exonic splicing enhancer TRA2-b
Summary
Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus (Order Bunyavirales; Family Phenuiviridae) (Adams et al, 2017) that is endemic to Africa and the Arabian Peninsula and causes disease in livestock and humans. RVFV causes abortive pregnancies and severe illness in young animals, while in humans it can cause a variety of symptoms, from mild flu-like. Species in the Aedes and Culex genera, are predicted to expand their range in response to climate change (Samy et al, 2016; Ryan et al, 2019; Iwamura et al, 2020), making RVFV a potential threat beyond Africa and the Arabian Peninsula. Because of its potential for severe illness and spread, RVFV is listed as a Category A overlap select agent by the CDC/ USDA. There is currently no licensed human vaccine or proven drug treatment for RVFV, and a deeper understanding of its replication and interaction with the host will be important for developing strategies to combat RVFV disease
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