Subcellular location of L1 retrotransposon-encoded ORF1p, reverse transcription products, and DNA sensors in lupus granulocytes.

Autor: Moadab F; Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA., Sohrabi S; Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA., Wang X; Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA., Najjar R; Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA., Wolters JC; Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Jiang H; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, NY, USA., Miao W; ROME Therapeutics, Boston, MA, USA., Romero D; ROME Therapeutics, Boston, MA, USA., Zaller DM; ROME Therapeutics, Boston, MA, USA., Tran M; Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA., Bays A; Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA., Taylor MS; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Kapeller R; ROME Therapeutics, Boston, MA, USA., LaCava J; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, NY, USA.; European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, The Netherlands., Mustelin T; Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA. tomas2@uw.edu.; University of Washington, 750 Republican Street, Room E507, Seattle, WA, 98109, USA. tomas2@uw.edu.
Jazyk: angličtina
Zdroj: Mobile DNA [Mob DNA] 2024 Jun 27; Vol. 15 (1), pp. 14. Date of Electronic Publication: 2024 Jun 27.
DOI: 10.1186/s13100-024-00324-x
Abstrakt: Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p.
Results: Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS. The DNA: RNA heteroduplexes vanished from the neutrophils when they were treated with a selective inhibitor of the L1 reverse transcriptase. We also report that ORF1p granules escape neutrophils during the extrusion of neutrophil extracellular traps (NETs) and, to a lesser degree, from neutrophils dying by pyroptosis, but not apoptosis.
Conclusions: These results bring new insights into the composition of ORF1p granules in SLE neutrophils and may explain, in part, why proteins in these granules become targeted by autoantibodies in this disease.
(© 2024. The Author(s).)
Databáze: MEDLINE
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