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

IF 4.7 2区 生物学 Q1 GENETICS & HEREDITY
Fatemeh Moadab, Sepideh Sohrabi, Xiaoxing Wang, Rayan Najjar, Justina C Wolters, Hua Jiang, Wenyan Miao, Donna Romero, Dennis M Zaller, Megan Tran, Alison Bays, Martin S Taylor, Rosana Kapeller, John LaCava, Tomas Mustelin
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引用次数: 0

Abstract

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.

狼疮粒细胞中 L1 逆转录酶编码的 ORF1p、逆转录产物和 DNA 传感器的亚细胞位置。
背景:系统性红斑狼疮(SLE)是一种慢性自身免疫性疾病,其病程难以预测,病情反复加重与较为稳定的病情交替出现。系统性红斑狼疮的特征是广泛的免疫激活和针对双链DNA的自身抗体,以及细胞中作为核酸聚集体存在的大量蛋白质,如Ro60、MOV10和L1逆转录病毒编码的ORF1p:结果:我们在此报告,这3种蛋白质在一部分系统性红斑狼疮粒细胞中共同表达和共定位,并集中在同样含有DNA的胞浆小点中:RNA异质双链和DNA传感器ZBP1,但不包括cGAS。DNA:RNA杂合双链消失了:中性粒细胞经 L1 逆转录酶选择性抑制剂处理后,DNA:RNA 杂合双链消失。我们还报告说,ORF1p颗粒在中性粒细胞胞外捕获物(NET)的挤出过程中从中性粒细胞中逸出,在较小程度上,也从因热凋亡而死亡的中性粒细胞中逸出,但不是凋亡:这些结果为了解系统性红斑狼疮中性粒细胞中ORF1p颗粒的组成提供了新的视角,并在一定程度上解释了为什么这些颗粒中的蛋白质会成为该疾病自身抗体的靶标。
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来源期刊
Mobile DNA
Mobile DNA GENETICS & HEREDITY-
CiteScore
8.20
自引率
6.10%
发文量
26
审稿时长
11 weeks
期刊介绍: Mobile DNA is an online, peer-reviewed, open access journal that publishes articles providing novel insights into DNA rearrangements in all organisms, ranging from transposition and other types of recombination mechanisms to patterns and processes of mobile element and host genome evolution. In addition, the journal will consider articles on the utility of mobile genetic elements in biotechnological methods and protocols.
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