Nuclear retention and RNA editing safeguard self-tolerance to immunogenic intron lariats

Abstract

Introns are excised as lariats and rapidly degraded upon linearization, leaving their post-splicing role unclear. Here, we investigate their immunoregulatory potential by analyzing the intron lariat landscape upon inhibition of the debranching enzyme DBR1. We find that lariats harboring transposable elements (TEs), especially inverted Alu repeats (IRAlus), elicit cell cycle-dependent activation of protein kinase R (PKR), but only in cells harboring a high burden, such as breast cancer. These immunogenic lariats are initially retained in the nucleus, but upon cytosolic release, they drive PKR activation and apoptosis. Exploiting this, we combine DBR1 depletion with anti-mitotic chemotherapy to enhance lariat-PKR interactions and promote cancer cell death in vitro and in vivo. We further show that A-to-I editing of IRAlus-containing lariats weakens their interaction with PKR and suppresses PKR activation. Our findings highlight two parallel molecular mechanisms to sustain self-tolerance to repeat-rich introns, revealing a vulnerability exploitable for anti-tumor therapy.