IGF2BP1 restrains immunogenic endogenous dsRNA to suppress innate immune activation
摘要
The accumulation of endogenous double-stranded RNA (dsRNA) triggers cytosolic innate immune response, yet how cells maintain tolerance to self-RNA remains incompletely understood. Here, we identify the oncofetal RNA-binding protein IGF2BP1 as a critical suppressor of endogenous dsRNA immunogenicity. Genetic ablation of IGF2BP1 in cancer cells and intestinal organoids caused the accumulation of immunogenic dsRNA, activated a viral-mimicry-like type I interferon response, and inhibited cell growth. Transcriptome-wide RNA-structure and protein–RNA interaction analyses showed that IGF2BP1 preferentially binds 3′-UTRs enriched in Alu elements and associates with the RNA helicase DHX9 and the adenosine deaminase ADAR1, two established regulators of endogenous dsRNA homeostasis. RNA isolated from IGF2BP1-deficient cells was sufficient to induce dsRNA-sensor expression in recipient cells, supporting the immunostimulatory potential of the accumulated RNA species. These findings establish IGF2BP1 as a regulator of self-RNA structural homeostasis and nominate its inhibition as a potential viral-mimicry-based strategy for cancer immunotherapy.
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