Nonsense-mediated decay controls a negative feedback loop in innate immune sensing.

Area of Science:

• Molecular Biology
• Immunology
• Virology

Background:

• Nonsense-mediated decay (NMD) is a crucial mRNA surveillance pathway that degrades aberrant transcripts.
• NMD regulates gene expression and isoform abundance under physiological conditions.
• During viral infections, NMD's role is complex, exhibiting both antiviral and proviral effects, necessitating further investigation.

Purpose of the Study:

• To investigate the involvement of NMD in double-stranded RNA (dsRNA) sensing during viral infection.
• To elucidate the mechanisms by which dsRNA sensing influences NMD activity.
• To understand how NMD modulation impacts innate immune responses to viral stimuli.

Main Methods:

• Utilized EIF4A2 exon 10B inclusion as a model for NMD-related alternative splicing during viral infection.
• Assessed the impact of dsRNA sensing on NMD activity.
• Investigated the roles of RNaseL and PKR in NMD inhibition.
• Quantified IFN-β induction, interferon-stimulated gene expression, and IRF3 activation.
• Measured dsRNA content and its effect on PKR and RNaseL activation and cell death.

Main Results:

• dsRNA sensing inhibits NMD, primarily through translational blockade mediated by RNaseL or PKR.
• NMD inhibition was found to limit the induction of IFN-β and interferon-stimulated genes, preceding IRF3 nuclear translocation.
• Inhibition of NMD reduced dsRNA levels, subsequently decreasing PKR and RNaseL activation and inflammasome-mediated cell death.
• These findings suggest NMD directly influences dsRNA sensing by modulating the dsRNA load.

Conclusions:

• dsRNA sensing during viral infection inhibits NMD via translational repression.
• This inhibition establishes a negative feedback loop that limits dsRNA sensing and prevents excessive activation of antiviral pathways.
• NMD plays a critical role in regulating innate immunity and inflammation by controlling the dsRNA load and shaping antiviral responses.