Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells
Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells
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DOI：
10.1038/s41423-020-0384-0
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发表时间：
2020-03-09
影响因子：
24.1
通讯作者：
Nakajima, Hiroshi
中科院分区：
文献类型：
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作者：
Suehiro, Ken-Ichi;Suto, Akira;Nakajima, Hiroshi
过敏性哮喘是由吸入屋尘螨（HDMs）引起的，主要由Th 2细胞介导。最近，Sox（SRY相关高迁移率组（HMG）盒）家族成员在各种免疫反应中的作用已被研究。然而，Sox 12，SoxC组的成员，在Th 2细胞分化和过敏性气道炎症中的作用仍然未知。我们发现Sox 12 mRNA在Th 2细胞分化过程中显著增加。在体内，HDM诱导的嗜酸性粒细胞浸润到肺和Th 2细胞分化在Sox 12（-/-）小鼠与对照Sox 12（+/-）小鼠相比，加剧。在体外，与对照Sox 12（+/-）CD 4（+）T细胞相比，在Th 2条件下培养的Sox 12（-/-）CD 4（+）T细胞增加了Th 2细胞因子和GATA 3蛋白的产生。重要的是，在Th 2条件下，Sox 12的强制表达降低了CD 4（+）T细胞中GATA 3的蛋白水平，而不影响mRNA表达。此外，Sox 12通过蛋白酶体途径诱导CD 4（+）T细胞中GATA 3的降解。因此，Sox 12增强了GATA 3的泛素化，这是由E3连接酶Fbw 7介导的。最后，我们发现Fbw 7敲低部分消除了Sox 12介导的CD 4（+）T细胞中GATA 3的抑制。综上所述，这些结果表明，Sox 12通过加速Fbw 7介导的GATA 3降解来抑制Th 2细胞分化，并减弱HDM诱导的过敏性炎症。
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.