The DLC-1 tumor suppressor is involved in regulating immunomodulation of human mesenchymal stem cells through interacting with the Notch1 protein
Abstract Immunomodulatory activities of human mesenchymal stem cells (hMSCs) have been widely accepted as the most critical function of the cells for exerting its therapeutic effects. The activities include the inhibition by hMSCs on pro-inflammatory CD4 + -T lymphocytes, and the release of immunomodulatory molecules, like IDO1. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previously, the Notch1 protein has been demonstrated to be able to promote the immunomodulation of hMSCs through inhibiting CD4 + -Th1 lymphocyte proliferation and enhancing IDO1 expression. The present study further revealed that it was the Notch1-Hey1 axis, rather than the Notch1-Hes1 axis, that was likely responsible for mediating the immunomodulation of the Notch1 signaling. Meanwhile, following a previously proposed hypothesis to identify proteasome-regulated protein(s) for limiting the activity of the Notch1 signaling in hMSCS, the DLC-1 tumor suppressor was identified to be such a candidate protein, which was subjected to protein degradation mediated by the DDB1 and FBXW5 E3 ligases . It was further shown that the DLC-1 signaling composing of DLC-1, Rock1 and FBXW5 proteins was involved in inhibiting the immunomodulation of hMSCs. More importantly, the immunomodulation was achieved through an interaction between the DLC-1-FBXW5-Rock1 signaling and the Notch1-Hey1 signaling . In fact, the present study a novel function of DLC-1 tumor suppressor as well as proposed a new mutual exclusion mechanism likely responsible for fine-tuning the immunomodulation of hMSCs.