2. Academic Validation
  3. Defects in intron recycling suppress the antiviral response via a mechanism of intronic endogenous dsRNA

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

  • J Exp Med. 2026 Apr 6;223(4):e20250344. doi: 10.1084/jem.20250344.
Chaorui Duan 1 2 3,  Luke Buerer 1 2 3,  Cory Bowers 1 2 3,  Allison J Taggart 1,  Mara H O'Brien 1 2 3,  Sarah Gunasekera 1 2 3,  Chien-Ling Lin 1 4,  Jing Wang 1,  Yi Zeng 5,  Jonathan P Staley 5,  Alger M Fredericks 6,  Sean F Monaghan 7,  Anastasia Welch 1,  Nathaniel E Clark 1,  Daxing Gao 8 9 10,  Nico Marr 11,  Shen-Ying Zhang 10 12 13,  Jean-Laurent Casanova 10 12 13 14 15,  William G Fairbrother 1 2 3
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, USA.
  • 2 Center for Computational Molecular Biology, Brown University , Providence, RI, USA.
  • 3 Giuliani RNA Center, Brown University , Providence, RI, USA.
  • 4 Institute of Molecular Biology, Academia Sinica , Taipei, Taiwan.
  • 5 Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL, USA.
  • 6 Department of Surgery, The Miriam Hospital, Providence, RI, USA.
  • 7 Division of Surgical Research, Department of Surgery, Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI, USA.
  • 8 Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
  • 9 Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 10 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • 11 Department of Human Immunology, Sidra Medicine, Doha, Qatar.
  • 12 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
  • 13 Paris Cité University, Imagine Institute , Paris, France.
  • 14 Howard Hughes Medical Institute , New York, NY, USA.
  • 15 Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris, France.
PMID: 41817448 DOI: 10.1084/jem.20250344
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.

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