Abstract
C-Maf plays an important role in regulating cytokine production in TH cells. Its transactivation of IL-4 is optimized by phosphorylation at Tyr21, Tyr92, and Tyr131. However, the molecular mechanism regulating its tyrosine phosphorylation remains unknown. In this study, we demonstrate that Tec kinase family member Tec, but not Rlk or Itk, is a tyrosine kinase of c-Maf and that Tec enhances c-Maf-dependent IL-4 promoter activity. This effect of Tec is counteracted by Ptpn22, which physically interacts with and facilitates tyrosine dephosphorylation of c-Maf thereby attenuating its transcriptional activity. We further show that phosphorylation of Tyr21/92/131 of c-Maf is also critical for its recruitment to the IL-21 promoter and optimal production of this cytokine by TH17 cells. Thus, manipulating tyrosine phosphorylation of c-Maf through its kinases and phosphatases can have significant impact on TH cell-mediated immune responses.
Highlights
C-Maf is a leucine-zipper transcription factor and plays an important role in TH cells
Similar to the result obtained from HEK 293T cells, tyrosine phosphorylation of c-Maf was enhanced in activated TH2 cells by ectopically expressed Tec, whereas c-Maf tyrosine phosphorylation was reduced by knocking down Tec (Fig 1D)
We have identified a tyrosine kinase/phosphatase pair of c-Maf: Tec and Ptpn22, which reciprocally regulate the phosphorylation of c-Maf at Tyr21/92/131 and subsequently c-Maf-dependent transactivation of IL-4
Summary
C-Maf is a leucine-zipper transcription factor and plays an important role in TH cells. It contains an N-terminal transactivation domain, which is connected to the C-terminal DNA binding domain through a hinge domain. It is induced by TCR/CD28 and ICOS signals and preferentially expressed in TH2, TH17, TFH (follicular helper T) and Tr1 [1,2,3,4]. It directly transactivates IL-4 and is critical for TH2 differentiation [5]. C-Maf is induced by IL-27 and works cooperatively with aryl hydrocarbon receptor to promote the development of Tr1 cells and their expression of IL-10 [8, 9]
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