Aim2 Couples With Ube2i for Sumoylation-Mediated Repression of Interferon Signatures in Systemic Lupus Erythematosus.
Aim2 Couples With Ube2i for Sumoylation-Mediated Repression of Interferon Signatures in Systemic Lupus Erythematosus.
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DOI：
10.1002/art.41677
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Meng G
中科院分区：
文献类型：
--
作者：
Lu A;Wu S;Niu J;Cui M;Chen M;Clapp WL;Barnes BJ;Meng G
系统性红斑狼疮（SLE）涉及肾脏损害，炎性体-caspase-1轴已被证明促进肾脏发病。本研究旨在探讨Aim2在SLE中的作用。雌性WT、Aim2−/−、Aim2−/−Ifnar1−/−、Aim2−/−Rag1−/−和Asc−/−小鼠在8-10周龄时腹腔注射500μl的pristane或生理盐水，每周监测生存情况2次，持续6个月。Aim2缺失而非Asc缺失导致普里坦注射小鼠SLE加重。Aim2−/−小鼠肾脏中免疫细胞浸润和I型干扰素（IFN-I）信号的增加与狼疮严重程度一致，阻断ifnar1介导的信号可减轻狼疮严重程度。适应性免疫细胞也参与了前列腺素攻击后Aim2−/−小鼠肾小球病变。重要的是，即使在没有pristane的情况下，Aim2−/−小鼠肾脏中的浆细胞样树突状细胞也比对照动物显著增加。因此，转录组分析显示，Aim2缺乏导致肾脏中ifn -i诱导基因的表达增强，甚至在早期发育阶段。在机制上，Aim2结合Ube2i，介导基于sumyly的IFN-I表达抑制；Aim2缺乏会降低细胞sumo化，导致IFN-I信号增强和肾脏发病机制。本研究表明Aim2在ube2介导的基于sumoylation的IFN-I生成和SLE发展的最佳抑制中发挥关键作用，因此Aim2- ube2i轴可以成为新的干预靶点。
Systemic lupus erythematosus (SLE) involves kidney damage, and the inflammasome-caspase-1 axis had been demonstrated to promote renal pathogenesis. The current study was designed to explore the function of Aim2 in SLE. Female WT, Aim2−/−, Aim2−/−Ifnar1−/−, Aim2−/−Rag1−/−, and Asc−/− mice at 8–10 weeks of age received one intraperitoneal injection of 500μl pristane or saline, and survival was monitored twice a week for 6 months. The absence of Aim2 but not Asc led to enhanced SLE in pristane-injected mice. Increased immune cell infiltration and type I interferon (IFN-I) signatures in the kidneys of Aim2−/− mice coincided with lupus severity, which was alleviated by blockade of Ifnar1-mediated signal. Adaptive immune cells were also involved in the glomerular lesions of Aim2−/− mice after pristane challenge. Importantly, even in the absence of pristane, plasmacytoid dendritic cells in the kidneys of Aim2−/− mice were significantly increased compared with control animals. Accordingly, transcriptome analysis revealed that Aim2 deficiency led to enhanced expression of IFN-I-induced genes in the kidney even at an early developmental stage. Mechanistically, Aim2 bound Ube2i, which mediates sumoylation-based suppression of IFN-I expression; deficiency of Aim2 decreased cellular sumoylation, resulting in an augmented IFN-I signature and kidney pathogenesis. This study demonstrates a critical role for Aim2 in an optimal Ube2i-mediated sumoylation-based suppression of IFN-I generation and development of SLE, the Aim2-Ube2i axis can thus be a novel target for intervention.
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影响因子：
13.3
作者：
Kahlenberg, J. Michelle;Yalavarthi, Srilakshmi;Zhao, Wenpu;Hodgin, Jeffrey B.;Reed, Tamra J.;Tsuji, Noriko M.;Kaplan, Mariana J.
通讯作者：
Kaplan, Mariana J.
影响因子：
19.6
作者：
Turner-Stokes T;Wilson HR;Morreale M;Nunes A;Cairns T;Cook HT;Pusey CD;Tarzi RM;Lightstone L
通讯作者：
Lightstone L
DOI：
10.1073/pnas.1802114115
发表时间：
2018-06-26
影响因子：
11.1
作者：
Crowl JT;Stetson DB
通讯作者：
Stetson DB
影响因子：
30.5
作者：
Decque, Adrien;Joffre, Olivier;Dejean, Anne
通讯作者：
Dejean, Anne
DOI：
10.4049/jimmunol.1502538
发表时间：
2016-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Corrales L;Woo SR;Williams JB;McWhirter SM;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF