Promotion of TLR7-MyD88-dependent inflammation and autoimmunity in mice through stem-loop changes in Lnc-Atg16l1

IF 14.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Nature Communications Pub Date : 2024-11-25 DOI:10.1038/s41467-024-54674-4
Zongheng Yang, Shuchen Ji, Lun Liu, Shuo Liu, Bingjing Wang, Yuanwu Ma, Xuetao Cao
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Abstract

Uncontrolled TLR signaling can cause inflammatory immunopathology and trigger autoimmune diseases. For example, TLR7 promotes pathogenesis of systemic lupus erythematosus. However, whether RNA structural changes affect nucleic acids-sensing TLRs signaling and impact disease progression is unclear. Here by iCLIP-seq we identify a TLR7-binding long non-coding RNA, Lnc-Atg16l1, and find that it promotes TLR7 and other MyD88-dependent TLRs signaling in various types of immune cells. Depletion of Lnc-Atg16l1 attenuates development of TLR7-linked autoimmune phenotypes in the mouse SLE model. Mechanistically, we find that Lnc-Atg16l1 binds to TLR7 at bases near U84 and MyD88 at bases around A129. The analysis of Lnc-Atg16l1 in situ structures show that it strengthens the interaction between TIR domain of TLR7 and MyD88 through specific stem-loop structure changes as a molecular scaffold after TLR7 activation to promote TLR7 downstream signaling. Therefore, we discover a mechanism for host RNA regulation of innate signaling and autoimmune disease through its structural changes. These findings provide insights into the pro-inflammatory function of self RNA in a structure-dependent manner and suggest a potential target for TLR-related autoimmune disorders.

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通过 Lnc-Atg16l1 的干环变化促进小鼠 TLR7-MyD88 依赖性炎症和自身免疫性
不受控制的 TLR 信号转导可导致炎症性免疫病理,诱发自身免疫性疾病。例如,TLR7 可促进系统性红斑狼疮的发病。然而,RNA结构的变化是否会影响核酸感应TLRs信号转导并影响疾病的进展尚不清楚。在这里,我们通过 iCLIP-seq 鉴定了一种与 TLR7 结合的长非编码 RNA(Lnc-Atg16l1),并发现它能在各种类型的免疫细胞中促进 TLR7 和其他依赖 MyD88 的 TLRs 信号转导。在小鼠系统性红斑狼疮模型中,删除 Lnc-Atg16l1 可减轻与 TLR7 相关的自身免疫表型的发展。从机理上讲,我们发现 Lnc-Atg16l1 与 TLR7 结合的碱基在 U84 附近,与 MyD88 结合的碱基在 A129 附近。对Lnc-Atg16l1原位结构的分析表明,Lnc-Atg16l1作为分子支架在TLR7激活后通过特定的茎环结构变化加强了TLR7的TIR结构域与MyD88之间的相互作用,从而促进了TLR7下游信号的传递。因此,我们发现了宿主 RNA 通过结构变化调控先天信号转导和自身免疫疾病的机制。这些发现深入揭示了自身 RNA 以结构依赖的方式促进炎症的功能,并提出了 TLR 相关自身免疫疾病的潜在靶点。
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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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