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Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells
Cellular & Molecular Immunology ( IF 21.8 ) Pub Date : 2020-03-09 , DOI: 10.1038/s41423-020-0384-0
Ken-Ichi Suehiro 1 , Akira Suto 1, 2 , Kensuke Suga 1 , Hiroki Furuya 1 , Arifumi Iwata 1 , Taro Iwamoto 1 , Shigeru Tanaka 1 , Takahiro Kageyama 1 , Kotaro Suzuki 1 , Koichi Hirose 1 , Véronique Lefebvre 3 , Hiroshi Nakajima 1
Affiliation  

Allergic asthma that is caused by inhalation of house dust mites (HDMs) is mainly mediated by Th2 cells. Recently, the roles of Sox (SRY-related high-mobility-group (HMG)-box) family members in various immune responses have been investigated. However, the roles of Sox12, a member of the SoxC group, in Th2 cell differentiation and allergic airway inflammation, remain unknown. We showed that Sox12 mRNA was significantly increased during Th2 cell differentiation. In vivo, HDM-induced eosinophil infiltration into the lung and Th2 cell differentiation were exacerbated in Sox12−/− mice compared with those in control Sox12+/− mice. In vitro, Sox12−/− CD4+ T cells that were cultured under Th2 conditions had increased production of Th2 cytokines and GATA3 protein compared with those of control Sox12+/− CD4+ T cells. Importantly, forced expression of Sox12 decreased the protein levels of GATA3 in CD4+ T cells under Th2 conditions without affecting mRNA expression. Furthermore, Sox12 induced degradation of GATA3 through the proteasome pathway in CD4+ T cells. Consistently, Sox12 enhanced ubiquitination of GATA3, which was mediated by the E3 ligase Fbw7. Finally, we found that Fbw7 knockdown partly abrogated Sox12-mediated GATA3 suppression in CD4+ T cells. Taken together, these results suggest that Sox12 suppresses Th2 cell differentiation by accelerating Fbw7-mediated GATA3 degradation, and attenuates HDM-induced allergic inflammation.



中文翻译:


Sox12 增强 Th2 细胞中 Fbw7 介导的 GATA3 泛素化和降解



因吸入屋尘螨 (HDM) 引起的过敏性哮喘主要由 Th2 细胞介导。最近,人们对 Sox(SRY 相关高迁移率基团 (HMG)-box)家族成员在各种免疫反应中的作用进行了研究。然而,Sox12(SoxC 组的成员)在 Th2 细胞分化和过敏性气道炎症中的作用仍不清楚。我们发现 Sox12 mRNA 在 Th2 细胞分化过程中显着增加。在体内,与对照 Sox12 +/-小鼠相比,HDM 诱导的嗜酸性粒细胞浸润肺部和 Th2 细胞分化在 Sox12 −/−小鼠中加剧。在体外,与对照Sox12 +/- CD4 + T细胞相比,在Th2条件下培养的Sox12 -/- CD4 + T细胞增加了Th2细胞因子和GATA3蛋白的产生。重要的是,Sox12的强制表达降低了Th2条件下CD4 + T细胞中GATA3的蛋白水平,而不影响mRNA表达。此外,Sox12 通过 CD4 + T 细胞中的蛋白酶体途径诱导 GATA3 降解。一致地,Sox12 增强了 GATA3 的泛素化,这是由 E3 连接酶 Fbw7 介导的。最后,我们发现 Fbw7 敲低部分消除了 CD4 + T 细胞中 Sox12 介导的 GATA3 抑制。综上所述,这些结果表明 Sox12 通过加速 Fbw7 介导的 GATA3 降解来抑制 Th2 细胞分化,并减轻 HDM 诱导的过敏性炎症。

更新日期:2020-04-24
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