GSE211812
Regulation of human interferon signaling by transposon exonization
Innate immune signaling is essential for clearing pathogens and damaged cells, and must be tightly regulated to prevent autoimmunity. Here, we found that the alternative splicing of exons derived from transposons 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 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. Overall design: Transcriptional profiling (RNA-seq) of HeLa cells cells (wild-type, IFNAR2-S KO, IFNAR2-L KO and IFNAR2-E7 KO) that were either untreated or stimulated with 10U/mL human recombinant interferon beta  (IFNb) for 4hrs.