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

Area of Science:

• Molecular Biology
• Immunology
• Virology

Background:

• Nonsense-mediated decay (NMD) degrades aberrant transcripts with premature termination codons.
• NMD regulates gene expression and isoform abundance under physiological conditions.
• NMD's role in viral infections is complex, exhibiting both antiviral and proviral activities.

Purpose of the Study:

• Investigate NMD's involvement in double-stranded RNA (dsRNA) sensing during viral infection.
• Clarify the discrepancies in NMD's antiviral versus proviral roles.
• Determine the impact of NMD inhibition on innate immune signaling.

Main Methods:

• Utilized EIF4A2 exon 10B inclusion as a model for NMD-regulated isoform accumulation during viral infection.
• Assessed the effect of dsRNA sensing on NMD activity.
• Measured interferon-beta (IFN-β) induction, interferon-stimulated gene expression, and activation of PKR and RNaseL.
• Evaluated IRF3 phosphorylation and nuclear translocation.
• Quantified dsRNA content and assessedपाकिस्तान-induced cell death.

Main Results:

• dsRNA sensing inhibits NMD, correlating with translational blockade.
• RNaseL activation primarily drives NMD inhibition, with PKR involvement in its absence.
• NMD inhibition limits IFN-β and interferon-stimulated gene induction, preceding IRF3 activation.
• NMD inhibition reduces PKR and RNaseL activation and Pakistan-induced cell death by lowering dsRNA levels.
• NMD appears to directly control dsRNA sensing by modulating dsRNA load.

Conclusions:

• NMD inhibition upon dsRNA sensing creates a negative feedback loop in innate immunity.
• This feedback mechanism shapes the dsRNA sensing pathway and innate immune response during viral infection.
• NMD plays a critical role in regulating the host's response to viral dsRNA.