Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells |
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Authors: | Ken-Ichi Suehiro,Akira Suto,Kensuke Suga,Hiroki Furuya,Arifumi Iwata,Taro Iwamoto,Shigeru Tanaka,Takahiro Kageyama,Kotaro Suzuki,Koichi Hirose,Vé ronique Lefebvre,Hiroshi Nakajima |
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Affiliation: | 1.Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba, Japan ;2.Institute for Global Prominent Research, Chiba University, Chiba, Japan ;3.Department of Surgery/Division of Orthopedic Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA USA |
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Abstract: | 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. |
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Keywords: | Sox12 Asthma GATA3 Th2 ubiquitination |
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