Defects in intron recycling suppress the antiviral response via a mechanism of intronic endogenous dsRNA
Year: 2026
Type: article
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.
DOI: 10.1084/jem.20250344
Authors: Chaorui Duan, Luke Buerer, Cory Bowers, Allison J. Taggart, Mara H. O’Brien, Sarah Gunasekera, Chien-Ling Lin, Jing Wang, Yi Zeng, Jonathan P. Staley, Alger M. Fredericks, Sean F. Monaghan, Anastasia Welch, Nathaniel E. Clark, Daxing Gao, Nico Marr, Shen-Ying Zhang, Jean-Laurent Casanova, William G. Fairbrother
Institutions: Brown University, Institute of Molecular Biology, Academia Sinica, Academia Sinica, University of Chicago, Miriam Hospital, Rhode Island Hospital, University of Science and Technology of China, Rockefeller University, Sidra Medical and Research Center, Inserm, Université Paris Cité, Human Genetic of Infectious Diseases, Institut des Maladies Génétiques Imagine, Hôpital Necker-Enfants Malades, Howard Hughes Medical Institute
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: G250961418, G282427092, G3224950185, Inborn errors of immunity underlying severe viral infection of the brainstem, G4574501711, G6224498365, A genomic approach to studying the life cycle of intron lariats, G9000162752, G9000281544, Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational Success
OpenAlex ID: W7135023918