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

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• The noncanonical NFκB pathway, initially linked to lymphoid organogenesis, is increasingly recognized for its role in innate immunity.
• RNA viruses can activate and exploit the noncanonical NFκB pathway during infection, often to disrupt type 1 interferon (IFN) transcription.
• Rift Valley fever virus (RVFV) is a significant pathogen affecting livestock and human health.

Purpose of the Study:

• To investigate the role of RIOK3 alternative splicing in RVFV infection.
• To determine the association between RIOK3 alternative splicing and the noncanonical NFκB pathway.
• To elucidate how RVFV (MP12 strain) might co-opt cellular pathways for its replication.

Main Methods:

• Analysis of RIOK3 mRNA splicing patterns following RVFV infection.
• Assessment of noncanonical NFκB pathway activation.
• Evaluation of the impact of RIOK3 splicing on IFN response and viral replication.

Main Results:

• RVFV (MP12 strain) infection leads to alternative splicing of RIOK3 mRNA, generating a truncated RIOK3 protein (X2 isoform).
• This alternative splicing inhibits the IFN response while simultaneously activating an NFκB-mediated inflammatory response.
• The alternative splicing of RIOK3 mRNA is directly associated with the activation of the noncanonical NFκB pathway.

Conclusions:

• Alternative splicing of RIOK3 mRNA is a key event during RVFV infection.
• RVFV appears to co-opt the noncanonical NFκB pathway, facilitated by RIOK3 alternative splicing, to suppress host antiviral defenses.
• This mechanism likely contributes to viral success and pathogenesis by modulating both IFN and NFκB signaling.