HUWE1 Causes an Immune Imbalance in Immune Thrombocytopenic Purpura by Reducing the Number and Function of Treg Cells Through the Ubiquitination Degradation of Ets-1.
HUWE1 Causes an Immune Imbalance in Immune Thrombocytopenic Purpura by Reducing the Number and Function of Treg Cells Through the Ubiquitination Degradation of Ets-1.
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HUWE1 通过泛素化降解 Ets-1 减少 Treg 细胞的数量和功能，从而导致免疫性血小板减少性紫癜的免疫失衡
DOI：
10.3389/fcell.2021.708562
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发表时间：
2021
影响因子：
5.5
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Li J;Xia Y;Fan X;Wu X;Yang F;Hu S;Wang Z
背景资料：免疫性血小板减少性紫癜（ITP）是一种自身免疫性出血性疾病，Treg细胞数量减少和免疫抑制功能障碍是ITP的关键促进因素。然而，它们在ITP发展中的机制尚未完全阐明。研究方法：采用实时荧光定量PCR和Western blot检测ITP患者外周血CD 4 + T细胞HUWE 1 mRNA和蛋白水平。采用流式细胞术、酶联免疫吸附试验和免疫抑制试验检测HUWE 1在ITP中的功能。此外，通过免疫沉淀、环己酰亚胺追踪试验、泛素实验和免疫荧光试验，探讨HUWE 1降低ITP患者Treg细胞数量和功能的机制。结果如下：ITP患者外周血CD 4 + T细胞HUWE 1表达水平升高，HUWE 1 mRNA表达水平与血小板计数、Treg细胞百分比呈负相关。干扰HUWE 1可增加Treg细胞数量，增强其免疫抑制功能，而HUWE 1过表达则产生相反的结果。HUWE 1与E26转化特异性1（Ets-1）相互作用，这种作用依赖于Ets-1（Thr 38）磷酸化水平的负调控，HUWE 1促进Ets-1蛋白的泛素降解，抑制Treg细胞分化，削弱其免疫抑制功能。体内试验证实HUWE 1抑制剂减轻了小鼠的ITP。总结：HUWE 1通过泛素化降解Ets-1，减少Treg细胞数量，削弱Treg细胞功能，从而导致ITP患者免疫失衡。
Background: Immune thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder and the decreased number and immunosuppressive dysfunction of Treg cells are key promoters of ITP. However, their mechanisms in ITP development have not been fully clarified. Methods: HUWE1 mRNA and protein levels in CD4+ T cells in peripheral blood from ITP patients were assessed by quantitative real-time PCR and Western blot. HUWE1 function in ITP was estimated using flow cytometry, enzyme-linked immunosorbent assay and immunosuppression assay. Besides, the HUWE1 mechanism in reducing the number and function of Treg cells in ITP was investigated by immunoprecipitation, cycloheximide-chase assay, ubiquitin experiment and immunofluorescence assay. Results: HUWE1 expression was elevated in CD4+ T cells in peripheral blood from ITP patients and HUWE1 mRNA level was negatively correlated with platelet counts and Treg cell percentage. Moreover, the interference with HUWE1 increased the number of Treg cells and enhanced its immunosuppressive function, and the HUWE1 overexpression produced the opposite results. For the exploration of mechanism, HUWE1 interacted with E26 transformation-specific-1 (Ets-1) and this binding was dependent on the negative regulation of the phosphorylation level of Ets-1 (Thr38) and HUWE1 facilitated the ubiquitin degradation of Ets-1 protein to restrain Treg cell differentiation and weaken their immunosuppressive functions. The in vivo assay confirmed that the HUWE1 inhibitor alleviated ITP in mice. Conclusion: HUWE1 induced the immune imbalance in ITP by decreasing the number and weakening the function of Treg cells through the ubiquitination degradation of Ets-1.
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影响因子：
4.6
作者：
Appel CK;Gallego-Pedersen S;Andersen L;Blancheflor Kristensen S;Ding M;Falk S;Sayilekshmy M;Gabel-Jensen C;Heegaard AM
通讯作者：
Heegaard AM
ETS 家族的五个成员 ELF-1、ETV-4、ETV-3L、ETS-1 和 ETS-2 上调人白细胞相关免疫球蛋白样受体 1 基因基本启动子活性
DOI：
10.18632/aging.101475
发表时间：
2018-06-18
期刊：
Aging
影响因子：
--
作者：
Cao Q;Yang S;Lv Q;Liu Y;Li L;Wu X;Qu G;He X;Zhang X;Sun S;Li B;An J;Hu T;Xue J
通讯作者：
Xue J
影响因子：
4.9
作者：
Aqrawi, Lara A.;Galtung, Hilde Kanli;Jensen, Janicke Liaaen
通讯作者：
Jensen, Janicke Liaaen
影响因子：
16.6
作者：
Hao Z;Sheng Y;Duncan GS;Li WY;Dominguez C;Sylvester J;Su YW;Lin GH;Snow BE;Brenner D;You-Ten A;Haight J;Inoue S;Wakeham A;Elford A;Hamilton S;Liang Y;Zúñiga-Pflücker JC;He HH;Ohashi PS;Mak TW
通讯作者：
Mak TW
影响因子：
4
作者：
Kirouac DC;Schaefer G;Chan J;Merchant M;Orr C;Huang SA;Moffat J;Liu L;Gadkar K;Ramanujan S
通讯作者：
Ramanujan S