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bioRxiv · 10.1101/2025.02.10.637371

PU.1 and TGF-β signaling transactivate CD103 expression in mast cells and dendritic cells: Opposite roles of GATA2 in the expression of mucosal mast cell-specific genes

Ishii, K.·Nagata, K.·Akimoto, Y.·Zhao, W.·Inoue, M.·Ito, N.·Kasakura, K.·Nishiyama, C.
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Abstract

Mucosal mast cells (MMCs) are distinguished from connective tissue MCs by the specific expression of integrin CD103 (E/{beta}7) and MC proteases Mcpt1 and Mcpt2. Although the expression of the Mcpt1 and Mcpt2 genes is cooperatively regulated by the transcription factor GATA2 and TGF-{beta} signaling in MMCs, the transcriptional mechanism of CD103 expression remains unknown. Here, we found that surface CD103 and Itgae mRNA levels were significantly increased by the knockdown (KD) of Gata2 in bone marrow-derived MCs (BMMCs), which was accelerated by a TGF-{beta} stimulation. Since the mRNA levels of Spi1 (encoding PU.1) were increased in Gata2 KD BMMCs, we examined the effects of PU.1 on CD103 expression. As expected, CD103 levels on BMMCs were significantly decreased by Spi1 KD and increased by Spi1 overexpression. Spi1 KD suppressed Itgae expression even in the presence of TGF-{beta} in BMMCs and peritoneal MCs, whereas Gata2 KD amplified the TGF-{beta}-induced increase in Itgae expression. The amount of PU.1 binding to the cis-element in the Itgae gene was significantly and moderately increased by Gata2 KD and the TGF-{beta} stimulation, respectively. Since PU.1 is an essential transcription factor for dendritic cells (DCs), we examined the role of PU.1 in CD103 expression on DCs. The KD experiment using BMDCs showed a significant decrease in CD103 levels in Spi1 siRNA-transfected BMDCs. We concluded that PU.1 affected CD103 expression on MMCs and DCs by transactivating the Itgae gene, and also that GATA2, which positively regulated the MMC-specific expression of Mcpt1 and 2, inhibited CD103 expression by repressing PU.1.

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Ishii, K., Nagata, K., Akimoto, Y., Zhao, W., Inoue, M., Ito, N., Kasakura, K., Nishiyama, C.. 2025-02-10. PU.1 and TGF-β signaling transactivate CD103 expression in mast cells and dendritic cells: Opposite roles of GATA2 in the expression of mucosal mast cell-specific genes. https://doi.org/10.1101/2025.02.10.637371

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