Regulation of human interferon signaling by transposon exonization, 2024, Pasquesi et al.

[SNT Gatchaman]

Regulation of human interferon signaling by transposon exonization
Giulia Irene Maria Pasquesi; Holly Allen; Atma Ivancevic; Arturo Barbachano-Guerrero; Olivia Joyner; Kejun Guo; David M. Simpson; Keala Gapin; Isabella Horton; Lily L. Nguyen; Qing Yang; Cody J. Warren; Liliana D. Florea; Benjamin G. Bitler; Mario L. Santiago; Sara L. Sawyer; Edward B. Chuong

Innate immune signaling is essential for clearing pathogens and damaged cells and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells.

By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues and functions as a decoy receptor that potently inhibits interferon signaling, including in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.

HIGHLIGHTS
• Long-read transcriptomes enable improved characterization of transposon exonization

• Exonization generates many robustly expressed alternative isoforms of immune genes

• IFNAR2-S is a primate-specific isoform of IFNAR2 that functions as a decoy receptor

• Dysregulation of IFNAR2 splicing is associated with human immune disease

Link | PDF (Cell) [Open Access]

 

[SNT Gatchaman]

Summary quotes from discussion —

our work reveals that alternative splicing of the IFNAR2-S isoform is a critical primate-specific mechanism that regulates sensitivity to type I IFN signaling. While multiple isoforms of human IFNAR2 were first characterized decades ago, their significance has remained understudied with the assumption that IFNAR2-L is the most highly expressed and the only functionally relevant isoform.

our work uncovers the relative expression of IFNAR2L and IFNAR2-S as a potentially key determinant of the severity of immune-mediated diseases. Dysregulated IFN signaling underlies aberrant responses to infection, autoimmune diseases including type I interferonopathies such as systemic lupus erythematosus, altered tumor immune phenotypes and is a hallmark of Down syndrome.

We speculate that interindividual variation in IFNAR2 isoform expression ratios—potentially due to non-coding disease variants—may drive differences in the severity of immune-related pathologies. For instance, over 90 single-nucleotide polymorphisms (SNPs) within the IFNAR2 locus have been associated with severe COVID-19.

our study demonstrates a further example of a TE exonization event that was co-opted to serve a critical immune regulatory function.

it is broadly assumed that most events are nonfunctional because exonized TEs typically reside in untranslated regions, are subject to nonsense-mediated mRNA decay, or are actively repressed by the splicing machinery. Our long-read transcriptomic analysis suggests that many immune genes express yet-uncharacterized isoforms generated by TE exonization […] Our work implicates TE exonization as an underappreciated process that fuels the evolution of species-specific isoforms and the emergence of new mechanisms of immune regulation.