Alternative Splicing of RIOK3 Engages the Noncanonical NFκB Pathway during Rift Valley Fever Virus Infection

Abstract

Although the noncanonical NFκB pathway was originally identified as a cellular pathway contributing to lymphoid organogenesis, in the past 20 years, its involvement in innate immunity has become more appreciated. In particular, the noncanonical NFκB pathway has been found to be activated and even exploited by some RNA viruses during infection. Intriguingly, activation of this pathway has been shown to have a role in disrupting transcription of type 1 interferon (IFN), suggesting a rationale for why this response could be co-opted by some viruses. Rift Valley fever virus (RVFV) is a trisegmented ambisense RNA virus that poses a considerable threat to domestic livestock and human health. Previously, we showed the atypical kinase RIOK3 is important for mounting an IFN response to RVFV infection of human epithelial cells, and shortly following infection with RVFV (MP12 strain), RIOK3 mRNA is alternatively spliced to its X2 isoform that encodes a truncated RIOK3 protein. Alternative splicing of RIOK3 mRNA has an inhibitory effect on the IFN response but also stimulates an NFκB-mediated inflammatory response. Here, we demonstrate alternative splicing of RIOK3 mRNA is associated with activation of the noncanonical NFκB pathway and suggest this pathway is co-opted by RVFV (MP12) to enhance viral success during infection.

The role of post-transcriptional regulation in SARS-CoV-2 infection and pathogenicity

“…For example, during herpes simplex virus-1 (HSV-1) infection, increasing methylation level of host mRNA and nuclear export result in a stronger antiviral response ( 7 ). Alternative splicing of mRNA is associated with activation of the noncanonical NF-κB pathway and this pathway is co-opted by Rift Valley fever virus to enhance viral success during infection ( 8 ). The published articles provide referential ideas and methods for SARS-CoV-2, there is similarity or difference compared to other virus.…”

Special Issue: “Innate Immunity to Virus Infection, 1st Edition”

“…Bisom et al conducted research to investigate the function of RIOK3 during Rift Valley Fever virus (RVFV) infection. They found that RVFV infection activated the noncanonical NF-κB pathway to weaken the antiviral IFN signaling response due to the production of the alternatively spliced RIOK3 X2 isoform, which encodes a truncated RIOK3 [ 5 ]. This finding will be helpful for deeply understanding the pathogenesis of RVFV through the regulation of the noncanonical NF-κB pathway to enhance viral replication.…”