Bacterial RNA sensing by TLR8 requires RNase 6 processing and is inhibited by RNA 2'O-methylation.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2024-11-01 Epub Date: 2024-10-03 DOI:10.1038/s44319-024-00281-9

Ivanéia V Nunes, Luisa Breitenbach, Sarah Pawusch, Tatjana Eigenbrod, Swetha Ananth, Paulina Schad, Oliver T Fackler, Falk Butter, Alexander H Dalpke, Lan-Sun Chen

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Abstract

TLR8 senses single-stranded RNA (ssRNA) fragments, processed via cleavage by ribonuclease (RNase) T2 and RNase A family members. Processing by these RNases releases uridines and purine-terminated residues resulting in TLR8 activation. Monocytes show high expression of RNase 6, yet this RNase has not been analyzed for its physiological contribution to the recognition of bacterial RNA by TLR8. Here, we show a role for RNase 6 in TLR8 activation. BLaER1 cells, transdifferentiated into monocyte-like cells, as well as primary monocytes deficient for RNASE6 show a dampened TLR8-dependent response upon stimulation with isolated bacterial RNA (bRNA) and also upon infection with live bacteria. Pretreatment of bacterial RNA with recombinant RNase 6 generates fragments that induce TLR8 stimulation in RNase 6 knockout cells. 2'O-RNA methyl modification, when introduced at the first uridine in the UA dinucleotide, impairs processing by RNase 6 and dampens TLR8 stimulation. In summary, our data show that RNase 6 processes bacterial RNA and generates uridine-terminated breakdown products that activate TLR8.

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TLR8 对细菌 RNA 的感应需要 RNase 6 处理，并受到 RNA 2'O- 甲基化的抑制。

TLR8 可感知单链 RNA（ssRNA）片段，这些片段通过核糖核酸酶（RNase）T2 和 RNase A 家族成员的裂解处理。这些 RN 的处理过程会释放出尿嘧啶和嘌呤末端残基，从而导致 TLR8 激活。单核细胞中 RNase 6 的表达量很高，但尚未分析这种 RNase 对 TLR8 识别细菌 RNA 的生理作用。在这里，我们展示了 RNase 6 在 TLR8 激活中的作用。经转分化成单核细胞样细胞的 BLaER1 细胞以及缺乏 RNASE6 的原代单核细胞在受到分离细菌 RNA（bRNA）刺激和感染活细菌时，都表现出抑制 TLR8 依赖性反应。用重组 RNase 6 预处理细菌 RNA 会产生片段，从而诱导 RNase 6 基因敲除细胞产生 TLR8 刺激。当在 UA 二核苷酸的第一个尿苷引入 2'O-RNA 甲基修饰时，会影响 RNase 6 的处理并抑制 TLR8 的刺激。总之，我们的数据表明，RNase 6 可处理细菌 RNA 并生成尿苷末端分解产物，从而激活 TLR8。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.