Mesenchymal stem cells (MSCs) are multipotent stem cells that can exert immunomodulatory capacity upon stimulation with pro-inflammatory cytokines. Our previous work has identified Cullin 4B (CUL4B), a scaffold protein in the CUL4B-RING E3 ligase (CRL4B) complex, as a key regulator in the differentiation of MSCs. Here, we demonstrate the critical role of CUL4B in regulating the immunosuppressive function of MSCs. When stimulated with pro-inflammatory cytokines, MSCs lacking CUL4B display enhanced immunosuppressive capacity, which is mediated by the elevated inducible nitric oxide synthase (iNOS). TGF-β signaling can suppress iNOS by inhibiting its transcription as well as promoting its protein degradation. We show that the CRL4B complex cooperates with PRC2 complex and HDACs to repress transcription of Dlx1 and Pmepa1, two inhibitors of TGF-β signaling, leading to decreased expression and accelerated degradation of iNOS. Our study unveils the CRL4B complex as a potential therapeutic target in promoting the immunosuppressive capacity of MSCs.

间充质干细胞（MSC）是多能干细胞，在促炎细胞因子的刺激下可以发挥免疫调节能力。我们之前的工作已确定 Cullin 4B (CUL4B)（CUL4B-RING E3 连接酶 (CRL4B) 复合物中的支架蛋白）是 MSC 分化的关键调节因子。在这里，我们证明了 CUL4B 在调节 MSC 免疫抑制功能中的关键作用。当用促炎细胞因子刺激时，缺乏 CUL4B 的 MSC 表现出增强的免疫抑制能力，这是由诱导型一氧化氮合酶 (iNOS) 升高介导的。 TGF-β 信号传导可以通过抑制 iNOS 转录并促进其蛋白质降解来抑制 iNOS。我们发现，CRL4B 复合物与 PRC2 复合物和 HDAC 协同抑制Dlx1和Pmepa1 （两种 TGF-β 信号传导抑制剂）的转录，导致 iNOS 表达减少并加速降解。我们的研究揭示了 CRL4B 复合物作为促进 MSC 免疫抑制能力的潜在治疗靶点。