Defects in intron recycling suppress the antiviral response via a mechanism of intronic endogenous dsRNA

Loss of the lariat debranching enzyme DBR1 causes cytoplasmic accumulation of intron lariats, but why this reduces cell-intrinsic immunity is unclear. Here, we show that intronic inverted repeats Alu (IR Alus), normally degraded after splicing, form long double-stranded RNA (dsRNA) structures when lariats escape recycling. Viral introns evolve under pressure to avoid dsRNA, whereas human introns are enriched for them. Using computational, immunostaining, and genomic approaches, we demonstrate that DBR1 deficiency elevates cytoplasmic dsRNA and attenuates RNase L and PKR signaling. Our data suggest high levels of IR Alu dsRNA titrate PKR, potentially providing a mechanistic explanation for viral susceptibility in DBR1-deficient cells. Cytoplasmic RIP-seq against dsRNA finds introns to be a more abundant source of IR Alus than 3' UTRs in WT cells. Our findings suggest the high load of IR Alus in introns creates a situation where the efficiency of lariat recycling is a powerful modulator of endogenous dsRNA levels in human cells.

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Publication Details

Journal
The Journal of Experimental Medicine
Published
2026-01-15
DOI
https://doi.org/10.1084/jem.20250344
Primary Topic
RNA regulation and disease
Type
article
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article

Defects in intron recycling suppress the antiviral response via a mechanism of intronic endogenous dsRNA

J. Casanova, Allison J. Taggart, Alger M. Fredericks, Sarah Gunasekera et al.
The Journal of Experimental Medicine
RNA regulation and disease
article

Defects in intron recycling suppress the antiviral response via a mechanism of intronic endogenous dsRNA

J. Casanova, Allison J. Taggart, Alger M. Fredericks, Sarah Gunasekera, Daxing Gao, Nico Marr, Cheng-Wei Lin, Sean F. Monaghan, Mara H. O’Brien, Nathaniel E. Clark, Anastasia Welch, Chaorui Duan, Yi Zeng, Jonathan P. Staley, William G. Fairbrother, Cory Bowers, Shen-Ying Zhang, Jing Wang, Luke Buerer
article en

Abstract

Loss of the lariat debranching enzyme DBR1 causes cytoplasmic accumulation of intron lariats, but why this reduces cell-intrinsic immunity is unclear. Here, we show that intronic inverted repeats Alu (IR Alus), normally degraded after splicing, form long double-stranded RNA (dsRNA) structures when lariats escape recycling. Viral introns evolve under pressure to avoid dsRNA, whereas human introns are enriched for them. Using computational, immunostaining, and genomic approaches, we demonstrate that DBR1 deficiency elevates cytoplasmic dsRNA and attenuates RNase L and PKR signaling. Our data suggest high levels of IR Alu dsRNA titrate PKR, potentially providing a mechanistic explanation for viral susceptibility in DBR1-deficient cells. Cytoplasmic RIP-seq against dsRNA finds introns to be a more abundant source of IR Alus than 3' UTRs in WT cells. Our findings suggest the high load of IR Alus in introns creates a situation where the efficiency of lariat recycling is a powerful modulator of endogenous dsRNA levels in human cells.

The Journal of Experimental MedicineVol. 223(4)
University of Science and Technology of China (CN), Qatar Airways (Qatar) (QA), Howard Hughes Medical Institute (US), Inserm (FR), Université Paris Cité (FR), Brown University (US), Rhode Island Hospital (US), Miriam Hospital (US), University of Chicago (US), Hospital for Sick Children Pediatric Center (US), Sidra Medical and Research Center (QA), Institute of Molecular Biology, Academia Sinica (TW), Human Genetic of Infectious Diseases (FR), Institut des Maladies Génétiques Imagine (FR), Rockefeller University (US)
Openalex Percentile: Top 25%
RNA regulation and disease
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