ANGPTL3 通过抑制 IL1R1 相关信号复合体的组装,对 IL-1β 诱导的 NF-κB 激活进行负向调节。

IF 5.3 2区 生物学 Q2 CELL BIOLOGY
Yu Zhang, Zi-Tong Zhang, Shi-Yuan Wan, Jing Yang, Yu-Juan Wei, Hui-Jing Chen, Wan-Zhu Zhou, Qiu-Yi Song, Shu-Xuan Niu, Ling Zheng, Kun Huang
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引用次数: 0

摘要

白细胞介素-1β(IL-1β)诱导的信号传导是调节炎症和免疫的最重要途径之一。由配体 IL-1β、IL-1 受体(IL-1R)1 型(IL1R1)和 IL-1R 辅助蛋白(IL1RAP)组成的受体复合物的组装启动了这种信号传导。然而,IL1R1 相关复合物是如何调控的仍是个谜。血管生成素样 3(ANGPTL3)是血浆甘油三酯清除的关键抑制因子,主要在肝脏中表达,以细胞内和细胞外分泌形式存在。目前,ANGPTL3 已成为治疗高甘油三酯血症及相关心血管疾病的极具潜力的药物靶点。然而,大多数研究都集中在 ANGPTL3 的分泌形式上,而对其在细胞内的作用还知之甚少。在此,我们报告了细胞内 ANGPTL3 在 IL-1β 触发的信号传导中起负调控作用。过表达 ANGPTL3 可抑制 IL-1β 诱导的 NF-κB 激活以及 HepG2、THP1 和 HEK293T 细胞中炎症基因的转录,而敲除或敲除 ANGPTL3 则会产生相反的效果。从机理上讲,ANGPTL3 通过其胞内 C 端纤维蛋白原样结构域与 IL1R1 和 IL1RAP 相互作用,并破坏了 IL1R1 相关复合物的组装。综上所述,我们的研究揭示了 ANGPTL3 在炎症中的新作用,它通过抑制 IL1R1 和 IL1RAP 之间的生理相互作用来维持肝脏的免疫耐受和平衡。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ANGPTL3 negatively regulates IL-1β-induced NF-κB activation by inhibiting the IL1R1-associated signaling complex assembly.

Interleukin-1β (IL-1β)-induced signaling is one of the most important pathways in regulating inflammation and immunity. The assembly of the receptor complex, consisting of the ligand IL-1β, the IL-1 receptor (IL-1R) type 1 (IL1R1), and the IL-1R accessory protein (IL1RAP), initiates this signaling. However, how the IL1R1-associated complex is regulated remains elusive. Angiopoietin like 3 (ANGPTL3), a key inhibitor of plasma triglyceride clearance, is mainly expressed in the liver and exists in both intracellular and extracellular secreted forms. Currently, ANGPTL3 has emerged as a highly promising drug target for hypertriglyceridemia and associated cardiovascular diseases. However, most studies have focused on the secreted form of ANGPTL3, while its intracellular role is still largely unknown. Here, we report that intracellular ANGPTL3 acts as a negative regulator of IL-1β-triggered signaling. Overexpression of ANGPTL3 inhibited IL-1β-induced NF-κB activation and the transcription of inflammatory genes in HepG2, THP1, and HEK293T cells, while knockdown or knockout of ANGPTL3 resulted in opposite effects. Mechanistically, ANGPTL3 interacted with IL1R1 and IL1RAP through its intracellular C-terminal fibrinogen-like domain and disrupted the assembly of the IL1R1-associated complex. Taken together, our study reveals a novel role for ANGPTL3 in inflammation, whereby it inhibits the physiological interaction between IL1R1 and IL1RAP to maintain immune tolerance and homeostasis in the liver.

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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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