Truncated IFI16 mRNA transcripts can control its viral DNA defense activity

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Interferon-inducible protein 16 (IFI16) is a crucial sensor of viral double-stranded DNA (dsDNA) and a member of the Aim2-like receptor (ALR) family.
• IFI16 possesses a complex structure including a pyrin domain (PYD), HIN domains, a nuclear localization sequence (NLS), and S/T/P repeats.
• Previous research identified five alternatively spliced transcripts (V1, V2, V9, V4, Vβ) encoding distinct IFI16 isoforms, alongside other registered but uncharacterized transcripts.

Purpose of the Study:

• To comprehensively investigate the presence and diversity of IFI16 transcripts in a healthy human population.
• To characterize novel IFI16 transcripts and isoforms and understand their structural and functional implications.
• To elucidate the mechanisms regulating IFI16 mRNA expression and their impact on protein functionality.

Main Methods:

• Analysis of IFI16 transcript presence in a healthy cohort.
• Identification and characterization of alternative splicing events.
• Bioinformatic construction of protein models for novel IFI16 isoforms.

Main Results:

• All previously described IFI16 alternative transcripts, except for six predicted ones, were detected in the healthy population.
• Two previously undescribed IFI16 transcripts, designated V10 and V11, were identified.
• The study identified a total of nine distinct IFI16 isoforms, with protein models constructed to predict functional alterations related to inflammasome assembly and viral DNA binding.
• Key regulatory mechanisms for IFI16 mRNA expression involve the insertion of non-coding regions and exon loss.

Conclusions:

• The IFI16 gene exhibits significant transcript diversity in healthy individuals, with nine identified isoforms.
• Novel transcripts (V10, V11) expand our understanding of IFI16's molecular landscape.
• The identified isoforms and regulatory mechanisms provide insights into IFI16's role in innate immunity, inflammasome formation, and viral dsDNA sensing.