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.

SUBMITTER: Suehiro KI 

PROVIDER: S-EPMC8245422 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature