SMURF1通过介导YY1泛素化激活cGAS/STING/IFN-1信号轴,加速狼疮性肾炎的进展。

IF 3.3 4区 医学 Q3 IMMUNOLOGY
Autoimmunity Pub Date : 2023-12-01 Epub Date: 2023-11-22 DOI:10.1080/08916934.2023.2281235
Xiaoyan Li, Sisi Tao, Zhiquan Xu, Yi Ren, Wei Xiang, Xiaojie He
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引用次数: 0

摘要

内质网应激(ERS)加重和足细胞凋亡在狼疮肾炎(LN)进展中起重要作用,但其机制尚不清楚。本研究探讨了SMURF1在LN进展过程中调控足细胞凋亡和ERS的作用。以MRL/lpr小鼠为活体LN模型。HE染色分析组织病理变化。用LN患者血清IgG (LN-IgG)处理小鼠足细胞(MPC5细胞)构建LN体外模型。采用CCK8法测定细胞活力。流式细胞术和TUNEL染色检测细胞凋亡。采用ChIP和/或双荧光素酶报告基因和/或Co-IP分析SMURF1、YY1和cGAS之间的相互作用。通过泛素化分析分析YY1的泛素化。我们的研究结果发现,LN患者血清样本中SMURF1、cGAS和STING mRNA水平明显升高,YY1水平下调。YY1上调可减少ln - igg诱导的ERS和足细胞凋亡。此外,SMURF1的上调通过使YY1泛素化降低了YY1蛋白的稳定性和表达。救援研究显示,YY1敲低可消除SMURF1下调对ln - igg诱导的ERS和足细胞凋亡的抑制作用。同时发现YY1通过抑制cGAS/STING/IFN-1信号轴的转录来减轻LN足细胞损伤。最后,SMURF1敲低抑制LN在体内的进展。简而言之,SMURF1上调通过调控YY1泛素化激活cGAS/STING/IFN-1信号轴,促进LN进展过程中足细胞的凋亡。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
SMURF1 activates the cGAS/STING/IFN-1 signal axis by mediating YY1 ubiquitination to accelerate the progression of lupus nephritis.

Aggravated endoplasmic reticulum stress (ERS) and apoptosis in podocytes play an important role in lupus nephritis (LN) progression, but its mechanism is still unclear. Herein, the role of SMURF1 in regulating podocytes apoptosis and ERS during LN progression were investigated. MRL/lpr mice was used as LN model in vivo. HE staining was performed to analyze histopathological changes. Mouse podocytes (MPC5 cells) were treated with serum IgG from LN patients (LN-IgG) to construct LN model in vitro. CCK8 assay was adopted to determine the viability. Cell apoptosis was measured using flow cytometry and TUNEL staining. The interactions between SMURF1, YY1 and cGAS were analyzed using ChIP and/or dual-luciferase reporter gene and/or Co-IP assays. YY1 ubiquitination was analyzed by ubiquitination analysis. Our results found that SMURF1, cGAS and STING mRNA levels were markedly increased in serum samples of LN patients, while YY1 was downregulated. YY1 upregulation reduced LN-IgG-induced ERS and apoptosis in podocytes. Moreover, SMURF1 upregulation reduced YY1 protein stability and expression by ubiquitinating YY1 in podocytes. Rescue studies revealed that YY1 knockdown abrogated the inhibition of SMURF1 downregulation on LN-IgG-induced ERS and apoptosis in podocytes. It was also turned out that YY1 alleviated podocytes injury in LN by transcriptional inhibition cGAS/STING/IFN-1 signal axis. Finally, SMURF1 knockdown inhibited LN progression in vivo. In short, SMURF1 upregulation activated the cGAS/STING/IFN-1 signal axis by regulating YY1 ubiquitination to facilitate apoptosis in podocytes during LN progression.

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来源期刊
Autoimmunity
Autoimmunity 医学-免疫学
CiteScore
5.70
自引率
8.60%
发文量
59
审稿时长
6-12 weeks
期刊介绍: Autoimmunity is an international, peer reviewed journal that publishes articles on cell and molecular immunology, immunogenetics, molecular biology and autoimmunity. Current understanding of immunity and autoimmunity is being furthered by the progress in new molecular sciences that has recently been little short of spectacular. In addition to the basic elements and mechanisms of the immune system, Autoimmunity is interested in the cellular and molecular processes associated with systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, type I diabetes, multiple sclerosis and other systemic and organ-specific autoimmune disorders. The journal reflects the immunology areas where scientific progress is most rapid. It is a valuable tool to basic and translational researchers in cell biology, genetics and molecular biology of immunity and autoimmunity.
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