Dual specificity phosphatase 12 deficiency reveals its role in maintaining T cell survival

Abstract

Dual specificity phosphatases (DUSPs) are protein phosphatases that regulate cellular signaling pathways by dephosphorylating threonine/serine and tyrosine residues on the substrates. DUSP12 mediates the regulation of Toll-like receptor signaling, cell cycle, hepatocyte metabolism, cardiac hypertrophy, and fibrosis. Moreover, a nonsynonymous mutation of DUSP12 has been identified in patients with T-cell-mediated autoimmune diseases. However, the regulatory roles and mechanisms of DUSP12 in T cells remain unclear. In this study, we investigated the functional regulation and molecular mechanism of DUSP12 in T cells using T cell-specific DUSP12 conditional knockout mice. We found that DUSP12 cKO mice had severe T-cell lymphopenia. More interestingly, DUSP12 cKO mice spontaneously developed systemic inflammation including splenomegaly and intestinal inflammation. Furthermore, our results showed that DUSP12 localized to mitochondria and was essential for mitochondria integrity and cellular oxidative stress in T cells. Using mass spectrometry analysis, western blotting, immunofluorescent staining, and proximity ligation assay, we identified a novel DUSP12-interacted protein in T cells. The functional regulation of DUSP12 on this novel protein in T cells was also explored. Our current results made a significant breakthrough in DUSP12 functions in T cells. Also, DUSP12 may serve as a potential biomarker and therapeutic target for inflammatory disease.