The Roles And Underlying Mechanisms Of Wip1 In Regulating Mouse Dendritic Cell Function

Dendritic cells are innate immune cells,which closely connect innate and adaptive immunity,and play a key role in host defense and inflammatory response.However,the underlying molecular mechanisms that regulate dendritic cell development and function are not yet clear.Wild-type p53-induced phosphatase 1(Wip1)plays a key regulatory role in the development and differentiation of T cells,B cells,neutrophils,and macrophages.Myeloid dendritic cells are derived from the same sources as neutrophils and macrophages,but the role of Wip1 in the development and differentiation of bone marrow-derived dendritic cells is unclear.We found that Wip1 was expressed in bone marrow-derived dendritic cells(BMDCs).To study the role of Wip1 in the development of dendritic cells,we used Wip1 gene knockout mice.Bone marrow cells of WT and Wip1-/-mice were isolated,and BMDCs were induced and cultured in vitro with recombinant cytokines IL-4 and GM-CSF.We found that when Wip1 is absent,the number of BMDCs decreases,the proliferation ability is suppressed,and the phenotype is over-mature.In vitro studies on the antigen-presenting function of dendritic cells revealed that Wip1-deficient BMDCs drive T cells to differentiate into Thl and Th17 while inhibiting Treg differentiation.Molecular mechanism studies indicate that the maturation and functional effects of BMDCs caused by Wip1 deficiency are mediated via the WHSC1-Rictor/mTORC2 pathway.On the other hand,Wip1 reduces the protein stability of WHSC1 by dephosphorylation,resulting in enhanced WHSC1 K48-linked polyubiquitination.Besides,Wip1 negatively regulates BMDCs development by suppressing glycolysis and mitochondrial function.Therefore,our findings identify an unrecognized function of Wip1 as a cell type-specific negative regulator of BMDCs development and activities through limiting the WHSC1-Rictor/mTORC2 pathway.