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Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells

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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Acknowledgements

We thank Dr. S. Hori for the Foxp3scurfy mice, Dr. M. Yamashita for pMX-IN-Sox12, and Ms. K. Nemoto, J. Iwata, and M. Yoshino for technical help. This work was supported in part by Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, the Japanese Government, the LGS (Leading Graduate School at Chiba University) Program, MEXT, and the Institute for Global Prominent Research, Chiba University, Japan. The sources of support for this work: this work was supported in part by Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, the Japanese Government, the LGS (Leading Graduate School at Chiba University) Program, MEXT, and the Institute for Global Prominent Research, Chiba University, Japan. Dr. S. Hori provided Foxp3scurfy mice, and Dr. M. Yamashita provided pMX-Sox12-IRES-NGFR.

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K. Suehiro, A.S., T.I., and S.T. conceived and designed the study; K. Suehiro, K. Suga, and A.S. acquired the data; K. Suzuki, K.H., H.F., A.I., and H.N. analyzed and interpreted the data; V.L. provided resources and interpreted the data; A.S. and H.N. wrote the paper.

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Correspondence to Akira Suto or Hiroshi Nakajima.

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Suehiro, KI., Suto, A., Suga, K. et al. Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells. Cell Mol Immunol 18, 1729–1738 (2021). https://doi.org/10.1038/s41423-020-0384-0

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