Phosphatase DUSP23 induces Th2-mediated allergic diseases by preventing GATA3 degradation 2253381

Abstract

Abstract Introduction Dual-specificity phosphatase 23 (DUSP23) is involved in the regulation of placental development and cell division. The role of DUSP23 in immune regulation remains unknown. Methods We studied the role of DUSP23 in T-cell function using DUSP23 knockout (KO) mice, T-cell-specific DUSP23 conditional knockout (T-DUSP23 cKO, DUSP23f/f;CD4-Cre) mice. We performed in vitro T-cell differentiation, KLH immunization mouse model, ovalbumin (OVA)-induced allergic asthma mouse model, and dinitrofluorobenzene (DNFB)-induced atopic dermatitis mouse model. The functional effects of these DUSP23 variants are being studied by mutagenesis and immunoblotting analysis. Results We found that IL-4 production of the KLH-restimulated T cells was significantly decreased by DUSP23 knockout. In vitro Th2 differentiation was reduced using splenic T cells from DUSP23 KO mice. The lung inflammation and the skin inflammation were attenuated by T-cell-specific DUSP23 conditional knockout. The Th2 cytokines such as IL-4, IL-5, and IL-13 levels in the bronchoalveolar-lavage fluid (BALF) and serum were significantly decreased in OVA-challenged DUSP23 cKO mice. Interestingly, DUSP23 overexpression induced GATA3 protein levels, whereas GATA3 protein levels were reduced in T-DUSP23 cKO T cells. Furthermore, DUSP23 prevented FBXW7-induced K48-linked ubiquitination and proteasomal degradation of GATA3 protein, leading to induction of GATA3 protein levels and subsequent Th2 cytokine production. Consistently, DUSP23 and GATA3 protein levels were increased in T cells from patients with Th2-biased asthma and atopic dermatitis (AD). Data mining of whole exome sequencing (WES) datasets derived from human AD patients showed that multiple DUSP23 gene variants occurred in AD patients. Conclusion Taken together, DUSP23 induces Th2-mediated inflammation by preventing FBXW7-mediated GATA3 degradation, contributing to Th2-mediated allergic diseases. Funding Source National Health Research Institutes, Taiwan Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)