MAGI1 inhibits interferon signaling to promote influenza A infection.
MAGI1 inhibits interferon signaling to promote influenza A infection.
复制标题
DOI：
10.3389/fcvm.2022.791143
复制
发表时间：
2022
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
--
作者：
我们已经表明，膜相关鸟苷酸激酶与反向结构域结构-1（MAGI 1），一个支架蛋白与六个PSD 95/DiscLarge/ZO-1（PDZ）域，参与调节内皮细胞（EC）激活和动脉粥样硬化在小鼠。除了引起急性呼吸道疾病外，甲型流感病毒（IAV）感染在动脉粥样硬化形成中起重要作用，并引发急性冠状动脉综合征和致命的心肌梗死。因此，本研究的目的是探讨MAGI 1在IAV诱导EC激活中的功能和调控。然而，EC感染IAV增加MAGI 1表达，MAGI 1耗尽抑制IAV感染，表明MAGI 1的诱导可能促进IAV感染。用氧化低密度脂蛋白（OxLDL）治疗内皮细胞增加MAGI 1表达和IAV感染，表明MAGI 1是IAV感染后血脂水平和患者预后之间的机制联系的一部分。我们的微阵列研究表明MAGI 1缺失的EC增加蛋白质表达和信号网络参与干扰素（IFN）的产生。具体而言，用IAV感染MAGI 1-null EC上调信号转导子和转录激活子1（STAT 1）、干扰素b1（IFNb 1）、粘病毒抗性蛋白1（MX 1）和2′-5′-寡腺苷酸合成酶2（OAS 2）的表达，并激活STAT 5。相比之下，MAGI 1过表达抑制Ifnb 1 mRNA和MX 1表达，再次支持MAGI 1介导的前病毒应答。MAGI 1缺失诱导MX 1的表达和病毒抑制。这些数据表明，IAV抑制MAGI 1耗尽可能，部分是由于MX 1诱导。最后，干扰素调节因子3（IRF 3）易位到细胞核中的IRF 3磷酸化的情况下，和IRF 3 SUMO化被废除MAGI 1-耗尽EC。这些数据表明MAGI 1通过维持IRF 3 SUMO化来抑制IRF 3活化。总之，IAV感染以MAGI 1表达依赖性方式通过抑制包括STAT和IRF 3活化和随后的MX 1诱导在内的抗病毒应答在EC中发生，并且MAGI 1在EC活化和上调前病毒应答中起作用。因此，MAGI 1的抑制是IAV诱导的心血管疾病的潜在治疗靶点。
We have shown that membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1), a scaffold protein with six PSD95/DiscLarge/ZO-1 (PDZ) domains, is involved in the regulation of endothelial cell (EC) activation and atherogenesis in mice. In addition to causing acute respiratory disease, influenza A virus (IAV) infection plays an important role in atherogenesis and triggers acute coronary syndromes and fatal myocardial infarction. Therefore, the aim of this study is to investigate the function and regulation of MAGI1 in IAV-induced EC activation. Whereas, EC infection by IAV increases MAGI1 expression, MAGI1 depletion suppresses IAV infection, suggesting that the induction of MAGI1 may promote IAV infection. Treatment of ECs with oxidized low-density lipoprotein (OxLDL) increases MAGI1 expression and IAV infection, suggesting that MAGI1 is part of the mechanistic link between serum lipid levels and patient prognosis following IAV infection. Our microarray studies suggest that MAGI1-depleted ECs increase protein expression and signaling networks involve in interferon (IFN) production. Specifically, infection of MAGI1-null ECs with IAV upregulates expression of signal transducer and activator of transcription 1 (STAT1), interferon b1 (IFNb1), myxovirus resistance protein 1 (MX1) and 2′-5′-oligoadenylate synthetase 2 (OAS2), and activate STAT5. By contrast, MAGI1 overexpression inhibits Ifnb1 mRNA and MX1 expression, again supporting the pro-viral response mediated by MAGI1. MAGI1 depletion induces the expression of MX1 and virus suppression. The data suggests that IAV suppression by MAGI1 depletion may, in part, be due to MX1 induction. Lastly, interferon regulatory factor 3 (IRF3) translocates to the nucleus in the absence of IRF3 phosphorylation, and IRF3 SUMOylation is abolished in MAGI1-depleted ECs. The data suggests that MAGI1 inhibits IRF3 activation by maintaining IRF3 SUMOylation. In summary, IAV infection occurs in ECs in a MAGI1 expression-dependent manner by inhibiting anti-viral responses including STATs and IRF3 activation and subsequent MX1 induction, and MAGI1 plays a role in EC activation, and in upregulating a pro-viral response. Therefore, the inhibition of MAGI1 is a potential therapeutic target for IAV-induced cardiovascular disease.
登录
查看更多内容
影响因子：
2.7
作者：
Hiyoshi, M.;Indalao, I. L.;Yano, M.;Yamane, K.;Takahashi, E.;Kido, H.
通讯作者：
Kido, H.
影响因子：
24
作者：
Kytomaa, Sonja;Hegde, Sheila;Vardeny, Orly
通讯作者：
Vardeny, Orly
影响因子：
5.3
作者：
Hirabayashi, S;Tajima, M;Hata, Y
通讯作者：
Hata, Y
DOI：
10.1083/jcb.201010051
发表时间：
2011-05-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Heo KS;Lee H;Nigro P;Thomas T;Le NT;Chang E;McClain C;Reinhart-King CA;King MR;Berk BC;Fujiwara K;Woo CH;Abe J
通讯作者：
Abe J
DOI：
10.1038/s41579-021-00542-7
发表时间：
2021-07
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Flerlage T;Boyd DF;Meliopoulos V;Thomas PG;Schultz-Cherry S
通讯作者：
Schultz-Cherry S